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Shields > Front of the book >
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Authors
Authors: Allingham, R. Rand
Title: Shields Textbook of Glaucoma, 6th Edition
Copyright ©2011 Lippincott Williams & Wilkins
> Front of Book > Authors
SENIOR AUTHOR
R. Rand Allingham MD
Richard and Kit Barkhouser Professor of Ophthalmology
Duke University School of Medicine
Chief Glaucoma Service
Duke Eye Center
Durham, North Carolina, USA
ASSOCIATE AUTHORS
Karim F. Dam JI, MD, MBA
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Professor of Ophthalmology
University of Alberta—Faculty of Medicine & Dentistry
Director, Ophthalmology Fellowship Programs
Royal Alexandra Hospital
Edmonton, Alberta, Canada
Sharon F. Freedman MD
Professor of Ophthalmology and Pediatrics
Duke University School of Medicine
Chief Pediatric Ophthalmology and Strabismus Service
Duke Eye Center
Durham, North Carolina, USA
Sayoko E. Moroi MD, PHD
Associate Professor of Ophthalmology and Visual Sciences
University of Michigan Medical School
Director, Glaucoma Fellowship Program
The University of Michigan W. K. Kellogg Eye Center
Ann Arbor, Michigan, USA
Douglas J. Rhee MD
Assistant Professor of Ophthalmology
Harvard Medical School
Associate Chief, Practice Development
Massachusetts Eye and Ear Infirmary
Boston, Massachusetts, USA
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Foreword
> Front of Book > Foreword
Foreword
Most of us, as we approach the “golden years” of life, can look back with joy and pride on how we watched our
children grow from infancy through adolescence to adulthood, with accomplishments well beyond the ability of
their parents. My feelings are much the same with this book. During its infancy in the early 1980s, it was small
and naïve, and it grew slowly over the next 20 years, due in large measure to kind encouragement from
generous readers. But the day came, as we crossed into the new century, when I could no longer fully provide
for the book—the remarkable advances in glaucoma on so many fronts were exceeding my ability to keep up—
and I was fortunate to have an extended family step in and author the fifth, and now this sixth, edition.
When I first approached each of them with the request to assume authorship of the book, to the person they did
not hesitate to agree (at least they showed no outward hesitation), for which I will always be profoundly grateful.
And it truly has been a family affair. My Duke partner and longtime friend, Dr. R. Rand Allingham, graciously
agreed to serve as managing author, despite his heavy load as Chief of the Duke Glaucoma Service, and
skillfully guided the preparation of the latest two editions. Three of the authors, in whom I take great pride, are
former Duke glaucoma fellows who have gone on to become leaders in our profession at major universities: Drs.
Karim F. Damji, University of Alberta; Sharon F. Freedman, Duke University; and Sayoko E. Moroi, University of
Michigan. The final author of the fifth edition was my Yale partner, Dr. George Shafranov, who has since gone
into private practice and has been replaced in the sixth edition by Dr. Douglas J. Rhee, also a rising star at the
Massachusetts Eye and Ear Infirmary in the fine tradition of Drs. Paul A. Chandler and W. Morton Grant.
Each of these talented friends has added immensely to the editions in their areas of expertise, and I am grateful
to them not only for taking the time from their busy practices to perpetuate this textbook but also for truly raising
it to a new level. Sales of the fifth edition have approached 9000, which is quite remarkable (I felt good if we
broke 2000 with the earlier editions). This success is undoubtedly due to the contributions of the team of
authors. They not only updated all the chapters with the latest advances but also added new chapters on
molecular genetics and clinical epidemiology and expanded information on evolving technologies, including
ultrasound and image analysis. They updated information on the clinical forms of glaucoma, most notably
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exfoliation syndrome, and greatly enhanced the chapters on filtering surgery, glaucoma drainage-device
surgery, and glaucoma surgery for children.
While the fifth edition was a vast improvement over the previous ones, the sixth edition offers even more. Two
special features are the addition of color illustrations throughout the book and the accompanying Internet
version (the latter is an example of how times are changing, since the Internet was not even heard of when the
book began).
A goal of this book from the beginning has been to base the content on a moderately extensive bibliography of
both the classic and recent literature and to provide balanced viewpoints where controversy exists. The authors
have adhered admirably to this goal, and I hope it will continue to be the foundation of any future editions.
Another strength of the book is its limited number of authors. Multiple-author textbooks, which are in the majority
today, have the advantage of providing viewpoints by many individuals in their area of expertise, but a book that
is written, rather than edited, by a small number of authors provides the advantages of more cohesiveness and
consistent style throughout the book. This means more work for each author, several of whom were responsible
for a dozen chapters or more, but I hope that this feature can also be perpetuated in future editions.
And so my hat is off to Rand, Karim, Sharon, Sy, and Doug for this latest accomplishment. I also want to again
thank Mr. Jonathan Pine and all those at Lippincott Williams & Wilkins for their continued support over these
past 30 years. Now I will sit back, like the proud parent, and watch with profound gratitude and admiration as
these good friends continue to advance our understanding of glaucoma for the ultimate goal of preserving the
precious gift of sight in our patients.
M. Bruce Shields
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Preface
> Front of Book > Preface
Preface
Nearly 30 years have passed since A Study Guide for Glaucoma was published by M. Bruce Shields in 1982.
The first edition of the series that we now know as Shields Textbook of Glaucoma, has been embraced by
generations of practitioners at all levels of training. No small measure of this book's popularity is the fact that it
has become the leading subspecialty textbook on the subject of glaucoma. This should come as no surprise
since the core qualities of simple organization and ease to read were adroitly established by Bruce Shields
himself.
Over the past few decades, we have witnessed a logarithmic expansion of information in all areas of science
and medicine. This certainly has been the case for the subspecialty of glaucoma, where our complete
armamentarium consisted of three drugs after which surgery was the next step. Ironically, the mainstay of our
treatment 30 years ago—pilocarpine, epinephrine, and systemic carbonic anhydrase inhibitors—is seldom, if
ever, used today. Now, joining timolol, prostaglandin analogs, a2-agonists, and topical carbonic anhydrase
inhibitors is a multitude of laser surgical treatments, with many more therapeutic interventions in development.
Similarly, technology for diagnosing and following glaucoma has undergone major changes. Optical coherence
tomography is an increasingly used technology that will likely replace fundus photography as a mainstay to
diagnose and monitor glaucoma. Keeping up with the broad advance in technology and treatment strategy is
challenging but is essential if we are to utilize this knowledge effectively for patient care.
It has been a great joy seeing how Shields Textbook of Glaucoma is also evolving. It is immediately apparent
that the sixth edition, like the field of glaucoma itself, continues to evolve. With the incorporation of full color,
there is a sharper sense of what one sees clinically. Additionally, Shields has taken its place on the Internet,
making it accessible almost anywhere or anytime. With increasing types of data, the ability to analyze and utilize
multiple types of information will only increase. The need to have rapid and accurate information immediately at
hand is becoming essential to the practice of medicine as the demands for higher efficiency and efficacy
continue.
As you open the sixth edition of Shields Textbook of Glaucoma, we hope you, the reader, will appreciate the
efforts of a dedicated team that values the tradition that was started so long ago.
R. Rand Allingham
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ACKNOWLEDGMENTS
> Front of Book > ACKNOWLEDGMENTS
ACKNOWLEDGMENTS
It has been a great pleasure and an honor to serve as the senior author of the sixth edition of Shields Textbook
of Glaucoma. What would seem a daunting task has been an exciting and enjoyable journey. This landmark
work, initiated almost 3 decades ago by Bruce Shields, has become the leading textbook on glaucoma
worldwide. What Bruce did himself now takes a dedicated and talented team. I have had the honor of sharing
this journey with four seasoned and gifted authors, Karim, Doug, Sy, and Sharon. Remarkably, this group has
managed to keep the passion and spirit of this great work. This is no small undertaking when one considers the
tidal wave of new information and technology that has occurred over the intervening years.
To assist us in this process has been the addition of a talented new member on our team, Cris Coren, our
manager, copyeditor, and amazing “fix it” person! Cris was selected and elected to this position by unanimous
decree of the authors and editor. She has seamlessly edited text, managed references and figures, improved
flow, and organized the authorship and editing process. Being a stickler for detail, Cris refined the language and
structure of Shields, not unlike a conductor for a symphony. In brief, Cris has made this edition of Shields better
while making the journey a true pleasure.
Of course, none of this would be possible without the many dedicated and talented persons at Lippincott
Williams & Wilkins who have shepherded this process from the beginning. Not only is this the first complete
four-color edition, it is also the first to have an online version. This enhances the value to our readership and
allows us to pursue new content in an increasingly wireless society. In particular, I would like to thank Eric
Johnson at Red Act Group for his steady encouragement and wise counsel; Emilie Moyer, who has worked her
magic on the appearance and “feel” of this edition; Jonathan Pine, a seasoned veteran at LWW whose oversight
and guiding hand have been crucial to our success over the years; and Purnima Narayanan and the talented
compositor and copyeditor teams at MPS Limited, a Macmillan Company, for their exceptional attention to detail
and professionalism. Thanks as well to Julie Cancio Harper, our “permissions guru,” for help with copyright
clearance; and Beth Jenkinson and Ryan McCammon, for valuable editorial assistance.
Of course, all success derives from family and friends. Bruce Shields remains the person I come to for advice,
counsel, and a heart-to-heart. Thank you, dear friend, for these many years together and those to come! My
undying gratitude goes to Robin Goodwin, who has, most would say miraculously, kept order in my professional
life at Duke for over 17 years. Erin, my daughter and soon-to-be English professor, who has been my “in-house”
resource for all things literate! Michael, my son and evolving ophthalmologist and scientist, I can only imagine
how the world of Ophthalmology will change in your lifetime. Of course, Anna, my wife, whose patience,
understanding, and support have been central to this and so many other undertakings.
Finally, I wish to thank all of you who read and benefit from the knowledge contained in these pages. Your kind
and constructive comments are critically important to us as we strive to provide lucid and useful information that
will help those who suffer from glaucoma.
Rand Allingham
I am grateful to Bruce and Rand for having provided the opportunity to participate in this undertaking, which I
regard as a privilege and an honor. I consider them exemplars par excellence. I have also enjoyed collaborating
with my coauthors and have learned many new things from them. Over the years, residents and fellows,
particularly from the Universities of Ottawa and Alberta, have offered many helpful suggestions. I am thankful for
their feedback and hope that users of this book continue to provide input. My wife, Salima, daughters, Safeera,
Nabeeha, and my parents, Fateh and Gulshan Damji, have provided incredible inspiration. I am particularly
indebted to Salima, whose extraordinary strength, encouragement, and understanding have made it a joy to
dedicate time and effort to this endeavor.
Karim Damji
I express my gratitude to my husband, Neil, and to our wonderful children, Rebecca and Benjamin, for
unwavering encouragement and support. I am grateful to Rand and Bruce for the privilege of participating in this
wonderful creation; to my coauthors for continuing to teach me so much about glaucoma; to Cris Coren for
making the process seamless and simple; and to Bruce Shields, my mentor, inspiration, and friend.
Sharon Freedman
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To my husband, Mike Fetters, and my four sons, Kori, Tomo, Kazu, and Taka, for understanding and supporting
my contributions to this book. I am grateful to Gale Oren and her staff for medical information and literature,
Richard Hackel and the photography staff for their support of this project, my coauthor colleagues and Cris
Coren for their patience and support of this project, and my mentor and friend Bruce Shields.
Sayoko (“SY”) Moroi
I would like to thank my lovely wife, Tina, for your continual support, patience, and encouragement. To our
daughters, Ashley and Alyssa, whose smiles and laughter bless our lives. To my father and mother, Dennis and
Serena Rhee, for your support and guidance. To Susan Rhee, for your understanding, and to all my families—
Rhee, Chang, Kim, and Chomakos. Finally, to my friends and coauthors, for the honor of working with you, and
to Bruce Shields, our inspiration.
Douglas Rhee
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Introduction: An Overview of Glaucoma
> Front of Book > Introduction: An Overview of Glaucoma
Introduction: An Overview of Glaucoma
HISTORICAL BACKGROUND
Although our modern understanding of glaucoma dates back only to the mid-19th century, this group of
disorders was apparently recognized by the Greeks as early as 400 BC. In Hippocratic writings, it appears as
“glaucosis,” in reference to the bluish-green hue of the affected eye (1). This term, however, was also applied to
a larger group of blinding conditions that included cataracts. Although an association with elevated intraocular
pressure (IOP) is found in 10th-century Arabian writings, it was not until the 19th century that glaucoma was
clearly recognized as a distinct group of ocular disorders.
SIGNIFICANCE OF GLAUCOMA
Glaucoma is a leading cause of irreversible blindness throughout the world. World Health Organization
statistics, published in 1995, indicate that glaucoma accounts for blindness in 5.1 million persons, or 13.5% of
global blindness (behind only cataracts and trachoma at 15.8 million persons, or 41.8% of global blindness, and
5.9 million, or 15.5%, respectively) (2). Worldwide, it has become the second most common cause of bilateral
blindness. Open-angle glaucoma and angle-closure glaucoma were estimated to affect approximately 66.8
million persons by the year 2000, with 6.7 million experiencing bilateral blindness (3).
In the United States, glaucoma is the second leading cause of blindness and the most frequent cause of
blindness among African Americans. The U.S. Department of Commerce's Bureau of the Census 1990
population data (provided by the National Society to Prevent Blindness in 1993) estimated the total number of
glaucoma cases among persons 40 years of age or older to be 0.5 million (5.6%) among African Americans and
1.5 million (1.7%) among whites and others (including Hispanics, Asians, and Native Americans). Glaucoma is
also the second most common reason for ambulatory visits to ophthalmologists in the United States by
Medicare beneficiaries and is the leading cause of such visits among African Americans. An analysis of a
random 5% subsample of 1991 Medicare beneficiaries (National Claims History File—Part B) revealed
approximately 223 office visits for glaucoma per 1000 patients among African Americans and 154 such visits for
whites (compared with 136 and 194 office visits, respectively, for cataracts) (4). Although glaucoma more
commonly affects older adults, it occurs in all segments of society, with significant health and economic
consequences (5), making it a major public health problem.
A DEFINITION OF GLAUCOMA
A Group of Diseases
The most fundamental fact concerning glaucoma is that it is not a single disease process. Rather, it is a large
group of disorders characterized by widely diverse clinical and histopathologic manifestations. This point is not
commonly appreciated by the general public, or even by a portion of the medical community, which frequently
leads to confusion. For example, a patient may have difficulty understanding why she has no symptoms with her
glaucoma, when a friend experienced sudden pain and redness with a disease of the same name. Another
individual may avoid the use of cold medications because the package inserts cautions against its use in
patients with glaucoma, but this caution is only warranted for certain types of glaucoma.
Terminology
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The term glaucoma should be used only in reference to the entire group of disorders, just as the term cancer is
used to refer to another discipline of medicine that encompasses many diverse clinical entities with certain
common denominators. When referring to a diagnosis, one of the more precise terms, such as chronic openangle glaucoma, should be used to indicate the specific type of glaucoma that the individual is believed to have.
Common Denominator
The common denominator of the glaucomas is a characteristic optic neuropathy, which derives from various risk
factors that include but are not limited to increased IOP (6). Although elevated IOP is clearly the most frequent
causative risk factor for glaucomatous optic atrophy, it is not the only factor; therefore, to define glaucoma on
the basis of ocular tension is unwise and in many instances misleading. Nevertheless, aqueous humor
dynamics, which are integrally related to ocular pressure, are critical to our understanding of glaucoma, not only
because they are the most common and best understood of the causative risk factors for glaucoma but also
because they are presently the only factors that can be controlled to prevent progressive optic neuropathy.
At present, current classifications of glaucoma are based on the multitude of initiating events that ultimately
leads to elevated IOP or the alterations in aqueous humor dynamics that are directly responsible for the
pressure increase. As continuous research expands modern knowledge of the various factors leading to
glaucomatous optic neuropathy, both classifications
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of glaucoma and approaches to management will no doubt change. The unraveling of the genetic underpinnings
of glaucoma continues at an accelerating rate. Most forms of this group of diseases are extremely complex. In
the end, however, this knowledge will greatly alter how we classify and treat the various forms of glaucoma. For
now, the most important point to recognize is that glaucomatous optic neuropathy causes progressive loss of
the visual field, which can lead to total, irreversible blindness if the condition is not diagnosed and treated
properly. In Section I, three crucial parameters—IOP, the optic nerve, and the visual field—are considered as
they relate to our current understanding of glaucoma.
Prevention of Blindness from Glaucoma
Once the blindness of glaucoma has occurred, there is no known treatment that will restore the lost vision. In
nearly all cases, however, blindness due to glaucoma is preventable. This prevention requires early detection
and proper treatment. Detection depends on the ability to recognize the early clinical manifestations of the
various glaucomas. Section II discusses the many forms of glaucoma and the clinical and histopathologic
features by which they are characterized. Appropriate treatment requires an understanding of the pathogenic
mechanisms involved, as well as a detailed knowledge of the drugs and operations that are used to control the
IOP. Section III considers the medical and surgical modalities that are used in the treatment of glaucoma.
REFERENCES
1. Fronimopoulos J, Lascaratos J. The terms glaucoma and cataract in the ancient Greek and Byzantine writers.
Doc Ophthal. 1991;77(4):369-375.
2. Thylefors B, Négrel AD, Pararajasegaram R, et al. Global data on blindness [review]. Bull World Health Org.
1995;73(1):115-121.
3. Quigley HA. Number of people with glaucoma worldwide [review]. Br J Ophthal. 1996;80(5):389-393.
4. Javitt JC. Ambulatory visits for eye care by Medicare beneficiaries. Arch Ophthal. 1994;112(8):1025.
5. Leske MC. The epidemiology of open-angle glaucoma: a review. Am J Epidemiol. 1983;118(2):166-191.
6. Van Buskirk EM, Cioffi GA. Glaucomatous optic neuropathy [review]. Am J Ophthal. 1992;113(4):447-452.
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2011/10/19
1 - Cellular and Molecular Biology of Aqueous Humor Dynamics
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Shields > SECTION I - The Basic Aspects of Glaucoma >
> Table of Contents > SECTION I - The Basic Aspects of Glaucoma > 1 - Cellular and Molecular
Biology of Aqueous Humor Dynamics
1
Cellular and Molecular Biology of Aqueous Humor Dynamics
The study of glaucoma deals with factors involved in the pathophysiology of progressive optic
neuropathy characterized by “cupping” of the optic disc. These factors include the following disciplines:
(a) clinical epidemiology, (b) clinical research and outcome studies, (c) pharmacology of glaucoma
therapeutics, (d) genetics, (e) embryology and development of ocular structures, and (f) basic science
investigations of the anterior and posterior segments of the ocular structures relevant to glaucoma.
Because the role of lowering intraocular pressure (IOP) as a treatment of glaucoma has been
substantiated by several prospective, randomized clinical trials (see Chapter 27), a logical place to begin
this study is with an overview of the basic anatomy of the structural determinants responsible for
aqueous humor dynamics. The basic anatomy of the optic nerve, retina, and choroid is presented in
Chapter 4.
Figure 1.1 Stepwise construction of a schematic model, depicting the relationship of structures involved
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in aqueous humor dynamics. A: Limbus. B: Main route of aqueous humor outflow (“conventional” or
trabecular outflow). C: Ciliary body (site of aqueous humor production and other outflow route of
“unconventional” or uveoscleral outflow). D: Iris and lens.
OVERVIEW OF THE ANATOMY
Aqueous humor has multiple physiologic functions throughout the various ocular structures. The two
main structures related to aqueous humor dynamics are the ciliary body, the site of aqueous humor
production, and the limbal region, which includes the trabecular meshwork, the principal site of aqueous
humor outflow. Figure 1.1 shows the close relationship between these two structures and the
surrounding anatomy.
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The limbus is the transition zone between the cornea and the sclera. On the inner surface of the limbus is
an indentation; the scleral sulcus, which has a sharp posterior margin; the scleral spur; and a sloping
anterior wall that extends to the peripheral cornea.
A sieve-like structure, the trabecular meshwork, bridges the scleral sulcus and converts it into a tube,
called the Schlemm canal. Where the meshwork inserts into the peripheral cornea, a ridge is created,
known as the Schwalbe line. The Schlemm canal is connected by intrascleral channels to the episcleral
veins. The trabecular meshwork, Schlemm canal, and the intrascleral channels make up the main route
of aqueous humor outflow
The ciliary body attaches to the scleral spur and creates a potential space, the supraciliary space,
between itself and the sclera. On cross section, the ciliary body has the shape of a right triangle, and the
ciliary processes (the actual site of aqueous humor production) occupy the innermost and anterior-most
portion of this structure in the region called the pars plicata (or corona ciliaris). The pars plicata region is
also composed of smooth muscle, which serves the important functions of accommodation and
uveoscleral outflow. The ciliary processes consist of 70 to 80 radial ridges (major ciliary processes),
between which are interdigitated an equal number of smaller ridges (minor or intermediate ciliary
processes) (1) Figure 1.2. The posterior portion of the ciliary body, called the pars plana (or orbicularis
ciliaris), has a flatter inner surface and joins the choroid at the ora serrata.
The anterior-posterior length of the ciliary body in the adult eye ranges from 4.6 to 5.2 mm nasally to
5.6 to 6.3 mm temporally, according to various reports, with the pars plana accounting for
approximately 75% of the total length. The most rapid phase of growth of the proportions of the pars
plana occurs between 26 and 35 weeks' gestation (2). At birth, these measurements are 2.6 to 3.5 mm
nasally and 2.8 to 4.3 mm temporally, and they reach three fourths of the adult dimen-sions by 24
months, with a constant ratio between pars plicata and pars plana (3).
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Figure 1.2 Gross anatomic view of the inside view of the anterior segment showing the radial ridges of
the ciliary processes at the pars plicata portion of the ciliary body.
The iris inserts into the anterior side of the ciliary body, leaving a variable width of the latter structure
visible between the root of the iris and the scleral spur, referred to as the ciliary body band. The lens is
suspended from the ciliary body by zonules and separates the vitreous posteriorly from the aqueous
humor anteriorly. The iris separates the aqueous humor compartment into a posterior and an anterior
chamber, and the angle formed by the iris and the cornea is called the anterior chamber angle. Further
details regarding the gonioscopic appearance of the anterior chamber angle are considered in Chapter 3.
With this basic outline of the anatomic structures that regulate aqueous humor dynamics, it is important
to review the development of these structures and other structures of the eye. Current clinical training
teaches clinicians to subclassify various ocular disease phenotypes among patients who have “outside”
ocular abnormalities (or ocular phenotypes) that often have a strong genetic component, which is
discussed in Chapter 8. (Another useful resource for information on human diseases with a genetic
component is “Online Mendelian Inheritance in Man,” or OMIM. It can be accessed at
www.ncbi.nlm.nih.gov.) As more disease genes are identified, the clinical phenotypic presentations,
which are an “outside in” approach to understand disease, will merge with an “inside out” approach,
whereby identified gene mutations and risk alleles are related to the ocular and systemic phenotypes.
Our knowledge of the human genome, which has approximately 30,000 genes (4), and proteinomics (5),
which is the study of proteins, will provide a blueprint for understanding individual variations in eye
anatomy and ocular disease presentations (6).
EMBRYOLOGY OF THE EYE
The eye shows incredible diversity among the various phyla from simple eye spots, through compound
eyes, to complex structures with a single lens and photoreceptor arrays (7). The developmental biology
of the vertebrate eye from surface ectoderm, neural crest, and mesodermal mesenchyme has been
extensively investigated (8). An overall schematic of eye development is summarized in Figure 1.3. The
tissue origin of the various ocular structures is summarized in Table 1.1.
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Ocular development from these three tissue sources involves complex, specific cell growth, and
differentiation processes, which are not fully understood. These complex processes involve carefully
timed expression of various growth factors and their receptors, other signaling molecules and their
pathways, transcription factors, and structural components (9). In general, the genes that regulate
development can be categorized into different functional classes as follows: (a) structural genes, such as
cytoskeletal components, which may be considered as “housekeeping” genes that carry out ubiquitous
biochemical and structural functions; (b) regulatory genes, such as transcription factors (i.e., molecular
switches that control mRNA production by other genes) and cell signaling molecules, which mainly
determine specialized expression of
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genes; and (c) cell-specific genes encoding for specialized proteins of a particular cell type within an
organ, such as the unique proteins expressed in the photoreceptors. Abnormalities in expression of the
individual genes or interaction among multiple genes caused by gene mutations or altered expression
can lead to congenital defects and human disease (Table 1.2).
Figure 1.3 Schematic of early eye development from the optic vesicle stage (A), lens placode stage (B),
and optic cup stage (C). During the optic cup stage (C), the neurogenesis of the retina proceeds in a
highly regulated process with ganglion cells differentiating first, followed by the amacrine cells, bipolar
cells, horizontal cell photoreceptors, and Müller (glial) cells. (Modified from Traboulsi El, ed. Genetic
Diseases of the Eye; 1998:12, 15. By permission of Oxford University Press.)
Table 1.1 Derivatives of Embryonic Tissues
Neuroectoderm
Cranial Neural Crest
Surface Ectoderm Mesoderm
Cells
Neurosensory
Corneal stroma and
Epithelium, glands, Fibers of extraocular; muscles
retina
endothelium
cilia of skin of lids, endothelial lining of all orbital
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Retinal pigment
epithelium
Sclera (see also
mesoderm)
and caruncle
Conjunctival
epithelium
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and ocular blood vessels;
temporal portion of sclera;
vitreous
Pigmented ciliary Trabecular meshwork
epithelium
Sheaths and tendons of Lens
Nonpigmented
extraocular muscles
ciliary epithelium
Lacrimal gland and
Connective tissues of iris drainage system
Pigmented iris
epithelium
Ciliary muscles
Vitreous
Sphincter and
Choroidal stroma
dilator muscles of
iris
Melanocytes (uveal and
epithelial)
Optic nerve, axons,
and glia
Meningeal sheaths of
the optic nerve
Vitreous
Schwann cells of ciliary
nerves
Ciliary ganglion
Most orbital bones,
cartilage, and
connective tissue of the
orbit
Muscular layer and
connective tissue sheaths
of all ocular and orbital
vessels
The following regulatory genes have been grouped into large families of transcription factors:
homeobox genes, zinc finger genes, and helix-loop-helix genes. Homeobox genes encode for a 60-amino
acid DNA-binding element and specifically determine the target gene for a transcription factor. These
genes are frequently involved in determining the regional identity of the embryo or individual fate and
differentiation of cells (10). Examples of homeobox genes include the PAX family and POU domain
family. The zinc finger family of genes is thought to be the most abundant of the transcription factors.
These genes
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share a common motif of a zinc atom binding to a group of histidine and cysteine amino acids and
holding together a small loop of amino acids. Examples of this gene family include the retinoic acid
receptors (RAR) and retinoid × receptor (RAX), which direct the binding of retinoic acid. Mutations in
these receptors have been associated with abnormal eye development (11). The helix-loop-helix family
of genes is characterized by two helical DNA-binding domains held together by a special domain or
region called as “leucine zipper” (12).
Table 1.2 Selected Genes Involved in Vertebrate Eye Development
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Gene (Gene Family) Function
BMP4 (TGF-ß)
Regulatory
BMP7 (TGF-ß)
Brn3B (POU
Domain)
Chx10 (Homeobox)
CRB1
CYP1B1
?-crystallin (ß?crystallins)
FoxCl
(FKHL7/FREAC3)
(Bicoid homeobox)
LMX1B
(Homeodomain)
Math3 (Basic HLH)
Mi (Basic HLH)
Myoc
NR2E3
ocrl-1 (Insitol
phosphatase)
Optx2 (Bicoid)
Otx1/2 (Homeobox)
Otx2 (Homeobox)
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Tissue Expression
Optic primordium
Animal Model
Human Disease
Mouse anterior
Not reported
segment dysgenesis,
IOP, abnormal teeth
Regulatory Optic primordium.
Mouse knockout— Not reported
cornea, kidney,
microphthalmia
skeleton
Mouse Polydactyly
Regulatory Retinal ganglion cells Mouse knockout— Not reported
optic nerve Mouse
hypoplasia
Transcription Retina, brain
Mouse ocular
Microphthalmia,
factor
retardation
cataracts, abnormal iris
sclerocornea
Structural
Retina
Drosophila
Leber congenital
photoreceptor
amaurosis, retinitis
abnormalities
pigmentosa
Regulatory
Mouse anterior
Congenital glaucoma
segment dysgenesis
Structural
Lens
Mouse eye lens
Coppock cataract,
obsolescence (Elo), congenital lamellar,
cataract
punctate, and nuclear
Regulatory Anterior segment of Mouse
Axenfeld-Rieger
the eye
hydrocephalus,
syndrome, anterior
skeletal and eye
segment dysgenesis
abnormalities
Regulatory Anterior segment of Mouse
Nail-patella syndrome
the eye
microphthalmia
with COAG
Regulatory
Regulatory Retinal pigment
Mouse
Waardenburg syndrome,
epithelium, pigment microphthalmia
type II Tietz Albinismcells
deafness syndrome
Structural
Trabecular meshwork. Fluid discharge in Juvenile glaucoma
cilizary body, iris
the Drosophilas
a
muscle
Regulatory Regulatory
Mouse retinal
Enhanced S cone
degeneration
syndrome, GoldmannFavre syndrome
Regulatory Lens, brain, kidney Mouse knockout
Lowe syndrome
function
without Lowe
Syndrome
phenotype
Retina
Mouse pituitary,
Anophthalmia
retinal. and optic
nerve hypoplasia
Regulatory Iris and ciliary
epithelium. ocular
brain seizures;
surface
mouse lacrimal
gland missing
Regulatory Retinal pigment
epithelium, optic
lethal
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Pax2 (Homeobox)
Regulatory
Pax6 (Homeobox)
Regulatory
PITX2 (Bicoid
homeobox)
Regulatory
POU (Brn3, RPF-1) Regulatory
nerve
Early optic nerve.
kidney defects
Lens, retina, nose,
brain
Mouse knockout—
eye, kidney
Mouse small eye,
Drosophila
“eyeless”
Page 7 of 225
Renal-coloboma
syndrome
Aniridia, anophthalmia,
Peters anomaly, brain,
nose defects, optic nerve
hypoplasia, coloboma,
microphthalmia
Axenfeld-Rieger
syndrome
Brain, pituitary, ocular Chicken, frog,
mesenchyme, cardiac mouse situs
mesenchyme, neural inversus
crest
Retinal ganglion cells Mouse knockout— Not reported
ganglion cell
hypoplasia
Oligodendrocytes
Mouse ganglion cellNot reported
degeneration
Thyroid receptor
Regulatory
(TR)
Xath5 (Basic HLH) Regulatory
a Skeletal muscle, heart, stomach, thyroid, trachea, bone marrow, thymus, prostate, small intestine,
colon, lung, pancreas, testis, ovary, spinal cord, lymph node, and adrenal gland.
TGF-ß, transforming growth factor beta; IOP, intraocular pressure; COAG, chronic open-angle
glaucoma; HLH, helix-loop-helix.
The role for these various structural, regulatory, and cellspecific genes in ocular development has been
most extensively examined thus far in the retina, which is highly complex and only partially understood
(12). Although not as extensively studied as retinal development, the anterior ocular segment, including
the ciliary body and lens (13), also has important and complex roles in the development of the normal
eye. The tissue origins of the ciliary epithelium, ciliary smooth muscle, and lens are listed in Table 1.1.
The lens induces differentiation of ciliary epithelium at the edge of the optic cup (Fig. 1.3), and the iris
develops later from the edge of the optic cup. The ciliary muscle and stroma differentiate after the ciliary
epithelium is formed. It is not clear when during gestation the ciliary epithelium becomes active to
secrete aqueous humor, but it is assumed to start very early after formation (14). As the IOP increases,
the eye grows. It is also believed that the increase in IOP provides the force to generate ciliary folds in
the ciliary body and to change the shape of the cornea (15).
Abnormalities in the development of the anterior chamber angle, or anterior segment dysgenesis, are
exemplified in Axenfeld-Rieger syndrome (see Chapter 14). Thus far, genes that have been shown most
frequently to cause anterior segment dysgenesis encode transcription factors that are important in early
development. These transcription factors include PITX2, PITX3, PAX6, FOXC1, FOXC2, and FOXC3
(16). In transgenic mice, the cell signaling molecule, bone morphogenetic proteins, and related signaling
molecules play an important role in normal development of the anterior segment (17).
An approach to study embryology of ocular structures is using data obtained through bioinformatics—a
discipline that integrates the study of genes, pathways, and function. Gene expression data, also known
as transcript or mRNA expression, may be gleaned in discrete ocular tissues and at various time points
in development (18). Such a “global” overview of gene expression in these discrete ocular tissues
enables us to hypothesize and to design studies to answer some fundamental cell biology questions
about these ocular structures. By comparing and contrasting the gene expression profiles of these
discrete ocular tissues at various stages of development and the impact of environmental exposures, we
will understand the function of these eye structures at the cellular and molecular level (see further
discussion in Chapter 8).
BIOLOGY OF AQUEOUS HUMOR INFLOW
The regulation of IOP is a complex physiologic trait that depends on (a) production of aqueous humor,
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(b) resistance to aqueous humor outflow, and (c) episcleral venous pressure.
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To reduce this highly complex and only partially understood situation to its simplest form, IOP is a
function of the rate at which aqueous humor enters the eye (inflow) and the rate at which it leaves the
eye (outflow). When inflow equals outflow, a steady state exists, and the pressure remains constant. The
remainder of this chapter deals with these inflow and outflow parameters and their complex
interrelationships with the IOP.
Cellular Organization of the Ciliary Body and the Ciliary Processes
The ciliary body is one of three portions of the uveal tract, or vascular layer of the eye; the other two
structures in this system are the iris and choroid. The ciliary body is composed of (a) muscle, (b) vessels,
(c) epithelia lining the ciliary processes, and (d) nerve terminals from the autonomic nervous system
(Fig. 1.4).
Ciliary Body Muscle
The ciliary muscle consists of two main portions: the longitudinal and the circular fibers (Fig. 1.4). The
longitudinal fibers attach the ciliary body to the limbus at the scleral spur. This portion of muscle then
runs posteriorly to insert into the suprachoroidal lamina (fibers connecting choroid and sclera) as far
back as the equator or beyond. The circular fibers occupy the anterior and inner portions of the ciliary
body and run parallel to the limbus. One-third portion of the ciliary muscle has been described as radial
fibers, which connect the longitudinal and circular fibers. The physiologic function and pharmacologic
action of parasympathomimetic agents as they relate to the ciliary muscle are discussed in Chapter 32.
Ciliary Body Vessels
On the basis of studies in primate and human eyes, the vessels of the ciliary body appear to have a
complex arrangement with collateral circulation on at least three levels (19, 20): (a) The anterior ciliary
arteries on the surface of the sclera send out lateral branches that supply the episcleral plexus and
anastomose with branches from adjacent anterior ciliary arteries to form an episcleral circle, (b) The
anterior ciliary arteries then perforate the limbal sclera. In the ciliary muscle, branches of these arteries
anastomose with each other as well as with branches from the long posterior ciliary arteries to form the
intramuscular circle. Divisions of the anterior ciliary arteries also provide capillaries to the ciliary
muscle and iris and send recurrent ciliary arteries to the anterior choriocapillaris. (c) The major arterial
circle lies near the iris root anterior to the intramuscular circle and is actually the least consistent of the
three collateral systems. Although the primate studies reveal a contribution from perforating anterior
ciliary arteries, microvascular casting studies of human eyes, as well as several nonprimate animals,
indicate that this “circle” is formed primarily, if not exclusively, by paralimbal branches of the long
posterior ciliary arteries, which begin dividing in the anterior choroid. In any case, the major arterial
circle is the immediate vascular supply of the iris and ciliary processes.
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Figure 1.4 Schematic of the three major components of the ciliary body: (1) the ciliary muscle,
composed of longitudina [LCM), radial, and circular (CCM) fibers; (2) the vascular system, formed by
branches of the anterior ciliary arteries (ACA) and long posterior ciliary arteries (LPCA), which form
the major arteria circle (MAC); and (3) the ciliary epithelium (CE), composed of an outer pigmented and
an inner nonpigmented layer.
Each ciliary process in primates is supplied by two branches from the major arterial circle: the anterior
and posterior ciliary process arterioles (20) (Fig. 1.5). Anterior ciliary process arterioles supply the
anterior and marginal (innermost) aspects of the major ciliary processes. These arterioles have luminal
constrictions before producing irregularly dilated capillaries within the processes, suggesting
precapillary arteriolar sphincters. This may represent the anatomic site of adrenergic neural influence on
aqueous humor production by regulation of blood flow through the ciliary processes. The posterior
ciliary process arterioles supply the central, basal, and posterior aspects of the major ciliary processes, as
well as all portions of the minor processes. These arterioles are of larger caliber than the anterior
arterioles and lack the constrictions seen in the latter vessels. Both populations of arterioles have
interprocess anastomoses.
Vascular casting studies of capillary networks in the ciliary processes of human eyes suggest three
different vascular territories with discrete arterioles and venules (19). The first is located at the anterior
end of the major ciliary processes and is drained posteriorly by venules without significant connections
to other venules in the ciliary processes. The second is in the center of the major processes, whereas the
third capillary network occupies the minor processes and posterior third of the major processes. Both of
the latter territories are drained by marginal venules, which are situated at the inner edge of the major
processes. It is thought that these three vascular territories may reflect a functional differentiation in the
process of aqueous humor production. Venous drainage is into choroidal veins, either from the posterior
aspects of the major and minor processes or by direct communication from the interprocess connections
(Fig. 1.6).
Ciliary Processes
The functional unit responsible for aqueous humor secretion is the ciliary process, which is composed of
(a) capillaries, (b) stroma, and (c) epithelia (Figs. 1.4 and 1.6). The ciliary process capillaries occupy the
center of each process. The thin endothelium has false “porous” areas of fused plasma
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P.9
membranes with absent cytoplasm, which may be the site of increased permeability. A basement
membrane surrounds the endothelium, and mural cells, or pericytes, are located within the basement
membrane (21).
Figure 1.5 Schematic of vascular interconnections of two contiguous major ciliary processes. Lateral
anterior arteriolar branches join to form interprocess capillary networks (arrowhead), which provide
communication between major processes. Laterally directed posterior arterioles form posterior
interprocess networks through which the minor ciliary processes receive blood. In addition, both anterior
and posterior interprocess networks drain directly into the choroidal veins (arrows). MAC, major arterial
circle. (From Morrison JC, Van Buskirk EM. Ciliary process microvasculature of the primate eye. Am J
Ophthalmol. 1984;97:372-383, with permission.)
A very thin stroma surrounds the capillary networks and separates them from the epithelial layers. The
stroma is composed of ground substance, consisting of mucopolysaccharides, proteins, and plasma
solutes (except those of large molecular size); very few collagen connective tissue fibrils, especially
collagen type III (22); and migrating cells of connective tissue and blood origin (21). Tubular
microfibrils with and without elastin have been demonstrated in bovine ciliary body, especially in the
stroma of the pars plana, in relation to zonules (23).
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Figure 1.6 Light microscopic view of ciliary processes, sectioned perpendicular to radial ridges, showing
major ciliary processes and minor ciliary processes from a human eye stained with toluidine blue.
Two layers of ciliary epithelium surround the stroma, with the apical surfaces of the two cell layers in
apposition to each other (Fig. 1.7). The pigmented epithelium has numerous melanin granules in the
cytoplasm and an atypical basement membrane on the stromal side.
In the nonpigmented epithelium, the basement membrane is composed of glycoproteins that are
immunoreactive for laminin and collagen types I, III, and IV (24). This membrane, which faces the
aqueous humor, is also called the internal limiting membrane and fuses with the zonules. The
nonpigmented epithelium stains less intensely than the pigmented layer for cytokeratin 18 but more so
for vimentin, with the predominant distribution in the crests of the pars plicata and the posterior pars
plana (25). It also stains with antibodies against S-100 protein (22). Another molecule with restricted
expression in the nonpigmented cells are the water channels aquaporin-1, which is also expressed in
trabecular meshwork endothelium, and aquaporin-4 (26). In transgenic knockout mice, which do not
express these water channels, IOP is significantly reduced compared within the wild-type mice, whose
water channels are normally expressed. The mechanism of IOP lowering is through reduction in
decreasing aqueous humor production, but not in outflow. Although these genetically modified mice
have a
P.10
P.11
phenotype of lower IOP, patients with aquaporin-1 mutations have normal IOP (27).
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Figure 1.7 Schematic of the ciliary epithelium summarizing the histology and junctional complexes (A),
physiology of ionic transport mechanisms (B), transmembrane signaling and enzymatic pathways and
other paracrine functions (C). A: The ciliary epithelium is composed of two layers containing nuclei (A)
with an outer pigmented layer (facing the stroma of the ciliary process) and inner nonpigmented layer
(facing and lining the posterior chamber). Apical surfaces are in apposition to each other. Basement
membrane (BM) lines the bilayer and constitutes the internal limiting membrane on the inner surface.
The nonpigmented epithelium is characterized by mitochondria, zonula occludens (ZO), and lateral and
surface interdigitations. The pigmented epithelium contains numerous melanin granules. Additional
intercellular junctions include desmosomes (D) and gap junctions (G). B: Overall, there is a net
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secretion (open arrows) of the cations (Na+, K+, and H+) and anions (Cl- and HCO3-), but there is also
some absorption (solid arrows) of these ions. The net effect is a negative charge (O) toward the posterior
chamber relative to the ciliary body stroma (©). The transfer of these ions proceeds primarily through a
transcellular route, or transport across the bilayer through some ion channels and transporters (black
rectangles) Transfer also occurs to a lesser extent through the paracellular route, or between the cells. C:
Aqueous humor secretion is highly regulated by multiple transmembrane receptor-mediated pathways
(GPCR, G-protein coupled receptor; G, G-protein; AC, adenylate cyclase; ATP, adenosine triphosphate;
cAMP, cyclic adenosine monophosphate; PLC, phospholipase C; PI, phosphatidyl inositol; DAG, diacyl
glycerol; IP3, inositol trisphosphate), enzymatic-mediated pathways (GA, carbonic anhydrase type II
[and possibly type IV]), and specialized transporters, such as the aquaporin type I channel (AQP1),
which has restricted expression in the nonpigmented ciliary epithelium. The precise localization to
pigmented versus nonpigmented and orientation on apical versus basolateral surfaces are unknown for
these pathways; thus, they are represented in a bilayer couplet. Other potential paracrine functions of the
ciliary epithelium include secretion of small peptides (granules).
A variety of intercellular junctions connect adjacent cells within each epithelial layer, as well as the
apical surfaces of the two layers (28). Such junctions include gap junctions, which are expressed by the
pigmented cells, the nonpigmented cells and the pigmented-nonpigmented cells, and tight junctions or
zonula occludens, which are expressed between the nonpigmented cells. It is primarily the zonula
occludens in the nonpigmented ciliary epithelium that creates an effective barrier to intermediate and
highmolecular-weight substances, such as proteins.
Electrophysiologic studies of rabbit ciliary epithelium suggest that all of the cells in the epithelium
function as a syncytium (29). Tight junctions create a permeability barrier between the nonpigmented
epithelial cells, which forms part of the blood-aqueous barrier. These tight junctions are said to be the
“leaky” type, in contrast to the “nonleaky” type in the blood-retinal barrier, and may be the main
diffusional pathways for water and ion flow. Microvilli separate the two layers of epithelial cells. In
addition, “ciliary channels” have been described as spaces between the two epithelial layers. These
channels may be related to the formation of aqueous humor in that they develop between the fourth and
sixth months of gestation, corresponding to the start of aqueous humor production.
The Autonomic Innervation of the Ciliary Body
Both sympathetic and parasympathetic nerve endings innervate the ciliary body (30). The sympathetic
fibers synapse in the superior cervical ganglion, and the postsynaptic fibers are distributed to the ciliary
body vessels. Because the ciliary epithelium is not innervated, it is thought that the catecholamine
neurotransmitters released from the sympathetic nerve endings “diffuse” to the adrenergic receptors on
the ciliary epithelium. Stimulation of these receptors increases aqueous humor secretion by the ciliary
epithelium (discussed further in the section on Molecular Mechanisms and Regulation of Aqueous
Humor Production).
The parasympathetic fibers originate from the Edinger-Westphal nucleus to innervate the ciliary
muscles. Stimulation of these nerve fibers releases acetylcholine, which then stimulates the cholinergic
receptors on the ciliary muscle. These activated receptors cause the ciliary muscle to contract, causing
accommodation by changing the shape of the crystalline lens. In addition, ciliary muscle contraction
reduces resistance to conventional aqueous humor outflow, or trabecular outflow, and may also affect
unconventional aqueous humor outflow, or uveoscleral outflow. The effect of the cholinergic pathway
on the trabecular outflow pathway is used pharmacologically in the treatment of glaucoma and is
discussed in Chapter 32.
Molecular Mechanisms and Regulation of Aqueous Humor Production
Aqueous humor is a dynamic intraocular fluid that is vital to the health of the eye. The precise
localization of aqueous humor production appears to be in the anterior portion of the pars plicata along
the tips or crests of the ciliary processes (Fig. 1.2). This region has increased basal and lateral
interdigitations, mitochondria, and rough endoplasmic reticulum in the nonpigmented ciliary epithelium;
more numerous fenestrations in the capillary endothelium; a thinner layer of ciliary stroma; and an
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increase in cell organelles and gap junctions between pigmented and nonpigmented epithelia (30).
Aqueous humor is derived from plasma within the capillary network of the ciliary processes. The
circulating aqueous humor enters the posterior chamber and flows around the lens and through the pupil
into the anterior chamber. Within the anterior chamber, a temperature gradient (cooler toward the
cornea) creates a convection flow pattern, which may occasionally be visualized clinically when a
patient has inflammation with circulating inflammatory cells. Initially, to reach the posterior chamber,
the various constituents of aqueous humor must traverse the three tissue components of the ciliary
processes, that is, the capillary wall, stroma, and epithelial bilayer. The principal barrier to transport
across these tissues is the cell membrane and related junctional complexes of the nonpigmented
epithelial layer, and substances appear to pass through this structure by the following processes: (a)
diffusion (lipid-soluble substances are transported through the lipid portions of the membrane
proportional to a concentration gradient across the membrane), (b) ultrafiltration (water and watersoluble substances, limited by size and charge, flow through theoretical “micropores” in the protein of
the cell membrane in response to an osmotic gradient or hydrostatic pressure), or (c) secretion
(substances of larger size or greater charge are actively transported across the cell membrane). The latter
process is mediated by transporters, which are proteins in the membrane, and requires the expenditure of
energy generated by adenosine triphosphate (ATP) hydrolysis (29).
Basic Physiologic Processes
The following simplified three-part scheme describes the basic physiologic processes involved in
aqueous humor production.
Accumulation of Plasma Reservoir
First, tracer studies suggest that most plasma substances pass easily from the capillaries of the ciliary
processes, across the stroma, and between the pigmented epithelial cells before accumulating behind the
tight junctions of the nonpigmented epithelium (30). This movement takes place primarily by diffusion
and ultrafiltration. Drugs that alter perfusion of the ciliary blood vessels may exert their influence on
IOP at this level (20).
Transport across Blood-Aqueous Barrier
Second, as mentioned previously, active secretion is a major contributor to aqueous humor formation
(29). This active transport takes place through selective transcellular movement of certain cations,
anions, and other substances across the blood-aqueous barrier formed by the tight junctions between the
nonpigmented epithelium (Fig. 1.7). The process of aqueous humor secretion is mediated by transferring
NaCl from the ciliary body stroma to the posterior chamber with water passively following. This
secretion occurs in three steps by uptake of NaCl from stroma to pigment epithelial cells by
P.12
electroneutral transporters, by passage of NaCl from pigmented to nonpigmented cells through gap
junctions, and finally by release of Na+ and Cl- through Na+,K+-activated ATPase and Cl- channels,
respectively.
At the first step of NaCl secretion, rabbit in vitro studies demonstrated that paired activity of Na+/H+
and Cl-/HCO-3 antiports may be the dominant mechanism in the pigmented epithelium. At the opposite
nonpigmented epithelial surface, release of Na+ through Na+,K+-activated ATPase with the
accompanying release of CP through ion channels is enhanced by agonists of A3 adenosine receptors
(A3ARs). These mechanisms were confirmed in vivo in a mouse model that showed that inhibitors of
Na+/H+ antiports lower IOP and that A3AR agonists and antagonists raise and lower IOP, respectively.
Carbonic anhydrase mediates the transport of bicarbonate across the ciliary epithelium through a rapid
interconversion between HCO-3 and CO2 (see details in Chapter 31). Bicarbonate formation influences
fluid transport through its effect on Na+, possibly by regulating the pH for optimum active transport of
Na+(31).
Other transported substances (see “Function and Composition of Aqueous Humor”) include ascorbic
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acid, which is secreted against a large concentration gradient by the sodium-dependent vitamin C
transporter 2, or SVCT2 (32), and certain amino acids, which are secreted by at least three carriers (33).
Osmotic Flow
Third, the osmotic gradient across the ciliary epithelium, which results from the active transport of the
above substances, favors the movement of other plasma constituents by ultrafiltration and diffusion. The
mechanisms by which water moves from the ciliary body stroma, across the ciliary epithelium, and into
the posterior chamber are complex and only partially understood. There is evidence that Na+ is the
driving cationic force (29). Supporting this concept is the restricted expression of the water channels,
aquaporin-1 and aquaporin-4, in the nonpigmented ciliary epithelium (26). A specific water channel
antagonist has not yet been identified. The functional significance of these channels has not been
extensively studied and the rare individuals with mutations of the gene encoding these water channels
have a normal IOP (55).
Rate of Aqueous Humor Production
The turnover of aqueous humor within the anterior chamber is estimated to be approximately 1.0% to
1.5% of the anterior chamber volume per minute (34). The rate at which aqueous humor is formed
(inflow) is measured in microliters per minute (as discussed in Chapter 2). By using the technique of
scanning ocular fluorophotometry in more than 519 healthy persons, the mean (±standard deviation
[SD]) rate of aqueous humor flow between 8 am and noon was 3.0 ± 0.8 µL/min (35). The normal range
(i.e., 95% of the sample) was 1.5 to 4.5 µ/min and showed a Gaussian distribution of flow rates. In 490
persons, the afternoon flow rate decreased to 2.7 ± 0.6 µ/min, while the mean rate in 180 persons
between midnight and 6 am was 1.3 ± 0.4 µL/min, with a range of 0.4 to 2.1 µL/min. A later study
showed that individuals show concordance in aqueous humor flow, whereby those individuals who show
a high aqueous flow in the morning also show a lower but relative higher flow at night (36). These
changes in aqueous humor flow throughout the day reflect a biological pattern, also known as circadian
rhythm, but the changes in this flow cannot account alone for the circadian patter in IOP (see modified
Goldmann equation in Chapter 3) (37).
Circadian Rhythm of Aqueous Humor Flow
As noted above, there is a circadian rhythm of aqueous humor flow in humans, with rates during sleep
being approximately one half of those in the morning. The mechanisms that control this biological
rhythm are only partly understood and cannot be overcome entirely by light, ambulation, or activity
level. The hormonal basis for the diurnal fluctuation in the rate of aqueous humor flow, or circadian
rhythm, in humans is not completely understood (35). The strongest evidence suggests that physiologic
changes in the level of circulating epinephrine available to the ciliary epithelia are the major driving
force. Topical epinephrine has been shown to stimulate flow by 19% during the day and by 47% during
the evening. Norepinephrine has also been shown to stimulate flow, but not as effectively as
epinephrine. In patients who have had surgical adrenalectomy, a normal circadian rhythm of aqueous
humor flow persists. In patients with Horner syndrome, where there is reduced or absent sympathetic
innervation on one side, the circadian flow pattern is maintained. Systemically administered melatonin,
hormones related to pregnancy, and antidiuretic hormone also do not appear to influence the normal
circadian rhythm of flow. The effect of corticosteroids is more complex, in that exogenous corticosteroid
appears to augment the effect of epinephrine-mediated stimulation of flow.
Other Factors Influencing Aqueous Humor Flow
Aqueous humor flow is also reduced in patients with diabetes mellitus, regardless of type (38). In
myotonic dystrophy, the relative hypotony has been attributed to both reduction inflow rate and
enhanced uveoscleral outflow route through the atrophic ciliary muscle (39). This causes a decrease in
inflow (96), possibly related to a disruption in ciliary epithelium (97). Aqueous humor production can be
reduced with inflammation (iridocyclitis) and by cyclodialysis (40).
In comparing different types of glaucoma, there are similar aqueous humor flow rates in patients with
normal-tension glaucoma and healthy persons (41). Patients with ocular hypertension showed flow
patterns similar to those of healthy persons during the morning hours, but the IOP and resistance to
outflow values were higher in the patients with ocular hypertension (42). In patients with pigment
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dispersion syndrome, aqueous humor flow rate was slightly higher than in control participants because
of the larger volume of the anterior chamber in the patients than in the controls (43). In patients with
chronic open-angle glaucoma (COAG), aqueous humor flow during sleep was higher than in controls
(44).
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With aging, there is a decline in aqueous humor production—2.4% to 3.2% per decade after 10 years of
age (45). There appears to be a trend of lower flow in women than in men, but this may be related to
small differences in the size of the ocular structures (35). An elevation of IOP was once thought to be
associated with a decline in aqueous humor production, which was referred to as “pseudofacility,” but it
is now understood that aqueous humor flow is pressure insensitive (35). The osmotic stress of drinking
1000 mL of water is associated with a significant increase in aqueous humor flow after 90 minutes (46).
Caffeine does not have any clinically significant effect on aqueous humor flow in the normal human eye
(47).
The pharmacologic agents that reduce aqueous humor flow in the treatment of glaucoma are discussed
in Section III. These agents include the (ß-adrenergic receptor antagonists or (ß-blockers (see Chapter
29), the nonspecific adrenergic and selective a2-adrenergic receptor agonists (Chapter 30), and the
carbonic anhydrase inhibitors (Chapter 31).
Function and Composition of Aqueous Humor
Function
The circulating aqueous humor has at least the following functions: (a) maintaining proper IOP, which is
important in early ocular development as well as in maintaining globe integrity throughout life; (b)
providing substrates and removing metabolites from the cornea, lens, and trabecular meshwork; (c)
delivering high concentrations of ascorbate; (d) participating in local paracrine signaling and immune
responses; and (e) providing a colorless and transparent medium as a part of the eye's optical system.
Composition
The following statements, summarized in Table 1.3, describe the general characteristics of aqueous
humor, expressed relative to plasma. Aqueous humor of both the anterior and the posterior chambers is
slightly hypertonic compared with plasma. It is acidic, with a pH of 7.2 in the anterior chamber (48).
The two most striking characteristics of aqueous humor are (a) a marked excess of ascorbate (15 times
greater than that of arterial plasma) and (b) a marked deficit of protein (0.02% in aqueous humor
compared with 7% in plasma) (32, 49, 50 and 51).
To illustrate the constant metabolic interchanges that occur with various ocular tissues, the cornea takes
glucose and oxygen from the aqueous humor and releases lactic acid and a small amount of CO2 into the
aqueous humor (52). The lens takes up glucose, K+, and amino acids from the aqueous humor and
generates lactate and pyruvate; however, close similarities in aqueous humor composition between the
phakic and aphakic eye of the same individual suggest that lens metabolism has practically no influence
on the composition of aqueous humor (53). The exchange between the vitreous and retina with aqueous
humor has been shown for amino acids and glucose passing into the vitreous from the aqueous humor
(33).
The relative concentrations of free amino acids in human aqueous humor vary, with ratios of aqueous
humor to plasma concentrations ranging from 0.08 to 3.14, supporting the concept of active transport of
amino acids (54). The concentrations of most other ions and non-electrolytes are very close to those in
the plasma, and conflicting statements in the literature primarily represent differences with regard to
species and measurement techniques. In general, human aqueous humor has a slight excess of chloride
and a deficiency of bicarbonate and CO2 (48, 55). Lactic acid is reported to be in relative excess in
human aqueous humor, although this determination varies widely with the technique of measurement.
Sodium in rabbits and glucose in human eyes show a relative deficiency in the aqueous humor (54).
Table 1.3 General Character of Human Aqueous Humor (Expressed Relative to Plasma)
Slightly hypertonic
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Acidic
Marked excess of ascorbate
Marked deficit of protein
Slight excess of
Chloride
Lactic acida
Slight deficit of
Sodium (rabbit study)
Bicarbonatea
Carbon dioxide
Glucose
Other reported constituents/features
Amino acids (variable concentrations)
Sodium hyaluronate
Norepinephrine
Coagulation properties
Tissue plasminogen activator
Latent collagenase activity
a Varies with measurement technique.
Other molecules that have been identified in human aqueous humor may be considered potential
paracrine signaling molecules (56), meaning that these molecules are circulated and distributed to local
tissues. Sodium hyaluronate, a glycosaminoglycan, was reported to have a mean value of 1.14 ± 0.46
mg/g in human aqueous humor obtained before cataract extraction, with no substantial difference in
patients with diabetes or glaucoma (57). Signaling molecules, such as the catecholamine,
norepinephrine, and nitric oxide, have been identified in human aqueous humor (58, 59). Various
components of the coagulation and anticoagulation pathways may be present in human aqueous humor
(60), with an overall trend toward fibrinolytic activity. Various components involved in the maintenance
of extracellular matrix have been detected in aqueous humor, which may influence the trabecular
meshwork activity and subsequently the IOP (61). Several growth factors, which are polypeptides
involved in the homeostatic balance of cells in a tissue, have been detected in human aqueous humor,
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and receptors for many of these factors have been identified on appropriate target tissues, such as
trabecular meshwork and cornea (56). Of interest, myocilin has been detected in normal aqueous humor,
but it is absent in the aqueous humor of patients with myocilin-associated glaucoma (62).
BIOLOGY OF AQUEOUS HUMOR OUTFLOW
As noted earlier, most of the aqueous humor leaves the eye at the anterior chamber angle through the
system consisting of trabecular meshwork, the Schlemm canal, intrascleral channels, and episcleral and
conjunctival veins. This pathway is referred to as the conventional or trabecular outflow. In the
unconventional or uveoscleral outflow, aqueous humor exits by passing through the root of the iris,
between the ciliary muscle bundles, then through the suprachoroidal-scleral tissues.
The relative contribution of these outflow pathways depends on the species studied. Furthermore, there
is an age-dependent change in aqueous humor outflow in both the trabecular and the uveoscleral
pathways. In general, the trabecular outflow in human eyes accounts for approximately 70% to 95% of
the aqueous humor egress from the eye, with the lower values corresponding to younger eyes and the
higher values corresponding to older eyes (63). The other 5% to 30% of the aqueous humor leaves
primarily by the uveoscleral outflow pathway, with a decline in the contribution of this pathway with
age (64). Whereas both total outflow facility and trabecular outflow facility also decline with age, the
relative contributions of trabecular and uveoscleral outflow show an age-related shift, with a relative
increase in the contribution in the trabecular pathway. Because uveoscleral outflow is relatively
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independent of IOP in the physiologic range, decreased uveoscleral outflow and increased trabecular
outflow resistance with age simply mean that IOP must increase sufficiently to drive a higher proportion
of total flow (which remains rather constant with age) across the increased trabecular resistance.
Cellular Organization of the Trabecular Outflow Pathway
Scleral Spur
The posterior wall of the scleral sulcus is formed by a group of fibers, the scleral roll, which run parallel
to the limbus and project inward to form the scleral spur (Fig. 1.1), which is composed of 75% to 80%
collagen and 5% elastic tissue (65). Myofibroblast-like scleral spur cells, in close association with
varicose axons characteristic of mechanoreceptor nerve endings, suggest there is a mechanism for
measuring stress or strain in the scleral spur, as might occur with ciliary muscle contraction or changes
in IOP (66).
Schwalbe Line
Just anterior to the apical portion of the trabecular meshwork is a smooth area, which varies in width
from 50 to 150 µm and has been called zone S (67). The anterior border of this zone consists of the
transition from trabecular to corneal endothelium and the thinning and termination of the Descemet
membrane. The posterior border is demarcated by a discontinuous elevation, called the Schwalbe line,
which appears to be formed by the oblique insertion of uveal trabeculae into limbal stroma. Clusters of
secretory cells, called Schwalbe line cells, have been observed just beneath this ridge in monkey eyes
and are believed to produce a phospholipid material that facilitates aqueous humor flow through the
canalicular system (68).
Trabecular Meshwork
As previously discussed, the scleral sulcus is converted into a circular channel, called the Schlemm
canal, by the trabecular meshwork. This tissue consists of a connective tissue core surrounded by
endothelium and may be divided into three portions: (a) uveal meshwork; (b) corneoscleral meshwork;
and (c) juxtacanalicular tissue, which is sometimes referred to as the cribriform layer (Fig. 1.8) (63).
Uveal Meshwork
This innermost portion is adjacent to the aqueous humor in the anterior chamber and is arranged in
bands or ropelike trabeculae that extend from the iris root and ciliary body to the peripheral cornea. The
arrangement of the trabecular bands creates irregular openings that vary in size from 25 to 75 µm across.
Corneoscleral Meshwork
This portion extends from the scleral spur to the anterior wall of the scleral sulcus and consists of sheets
of trabeculae that are perforated by elliptical openings. These holes become progressively smaller as the
trabecular sheets approach the Schlemm canal, with a diameter range of 5 to 50 µm. The anterior
tendons of the longitudinal ciliary muscle fibers insert on the scleral spur and posterior portion of the
corneoscleral meshwork. This anatomic arrangement suggests an important mechanical role for the
cholinergic innervation of ciliary muscle on trabecular meshwork function.
Both the uveal and corneoscleral trabecular bands or sheets are composed of four concentric layers.
First, an inner connective tissue core is composed of typical collagen fibers with the usual 640 Å
periodicity. Indirect immunofluorescent studies of human trabecular meshwork indicate that the central
core contains collagen types I and III and elastin (69). Second, “elastic” fibers are composed of
otherwise typical collagen, arranged in a spiraling pattern with an apparent periodicity of 1000 Å. These
spiral fibrils may wind loosely or tightly and may provide flexibility to the trabeculae. Third, “glass
membrane” is a name given to the layer between the spiraling collagen and the basement membrane of
the endothelium. It is a broad zone composed of delicate filaments embedded in a ground substance
(70). Fourth, an outer endothelial layer provides a continuous covering over the trabeculae.
The trabecular endothelial cells are larger, are more irregular, and have less prominent borders than
corneal endothelial cells. They are joined by gap junctions and desmosomes, which provide stability, but
allow aqueous humor to freely traverse
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the patent endothelial clefts (71). Two types of microfilaments have been found in the cytoplasm of
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human trabecular endothelium. Sixty Å filaments are located primarily in the cell periphery, around the
nucleus, and in cytoplasmic processes. These appear to be actin filaments (72), which are involved in
cell contraction and motility, phagocytosis, pinocytosis, and cell adhesion. Intermediate filaments of 100
Å are more numerous in the cells and are composed of vimentin and desmin, according to
immunocytochemical studies of cultured human trabecular cells (73). These molecular markers in the
trabecular endothelial cells suggest a myocyte or muscle cell-like phenotype, which further implies
important contractile and motility functions.
Figure 1.8 Three layers of trabecular meshwork (shown in cutaway views): uveal, corneoscleral, and
juxtacanalicular.
Juxtacanalicular Tissue
This portion of the trabecular meshwork differs histologically from the other parts of the meshwork and
has been given various names, including juxtacanalicular connective tissue, pore tissue, cribriform layer,
and endothelial meshwork, depending on how one defines the anatomic limits of the tissue. In the
broadest sense, this structure has three layers, discussed here beginning with the innermost portion. The
inner trabecular endothelial layer is continuous with the endothelium of the corneoscleral meshwork and
might be considered as a part of this layer. The central connective tissue layer has variable thickness and
is unfenestrated with several layers of parallel, spindle-shaped cells loosely arranged in a connective
tissue ground substance (168, 177). This tissue contains collagen type III but no collagen type I or
elastin (69). Connective tissue cells in human and rabbit trabecular meshwork contain coated pits and
coated vesicles in the plasma membrane, which are involved in receptor-mediated endocytosis (74).
The outermost portion of the trabecular meshwork—that is, the last tissue that aqueous humor must
traverse before entering the canal—is the inner wall endothelium of the Schlemm canal. This endothelial
layer has significant morphologic characteristics, which distinguish it from the rest of the endothelium in
both the trabecular meshwork and in the Schlemm canal. The surface is bumpy due to protruding nuclei,
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cyst-like vacuoles, and fingerlike projections bulging into the canal (75, 76). The fingerlike projections
have been described as endothelial tubules with patent lumens, although there is lack of agreement as to
whether they communicate between the anterior chamber and Schlemm canal (77). Actin filaments, as
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previously described in the uveal and corneoscleral trabecular endothelium, are also present in the inner
wall endothelium of Schlemm canal (72).
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Figure 1.9 A: Light microscopic view of the Schlemm canal (SC) and adjacent trabecular meshwork
(TM) of normotensive Rhesus monkey eye. Trabecular wall of the Schlemm canal (TW) with prominent
vacuolated cells (arrows); corneoscleral wall of the Schlemm canal (CW); collector channel (CC).
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(Toluidine blue stain, × 1030.) (From Tripathi RC. Ultrastructure of the trabecular wall of the Schlemm
canal in relation to aqueous humor outflow. Exp Eye Res. 1968;7:335, with permission.) B: Electron
microscopic view of trabecular wall of SC of normotensive human eye, showing vacuolated endothelial
cells (V) containing flocculent material (FL). OZ, occluding zonules; BM, basement membrane; OS,
open spaces in endothelial meshwork (× 15,000). (From Tripathi RC. Ultrastructure of the trabecular
wall of Schlemm's canal: a study of normotensive and chronic simple glaucomatous eyes. Trans
Ophthalmol Soc U K. 1970;89:449-465, with permission.)
The intercellular spaces are 150 to 200 Å wide and the adjacent cells are connected by various
intercellular junctions. It is not clear as to how tightly these junctions maintain the intercellular
connections, although they will open to permit the passage of red blood cells (78). Zonula occludens
have been demonstrated in primate studies, which are traversed by meandering channels of extracellular
space or slit pores, although it is estimated that this accounts for only a small fraction of the aqueous
humor that leaves the eye by the conventional route (71).
Openings in the inner wall endothelium of the Schlemm canal have been described, and in general, the
openings consist of minute pores and giant vacuoles that vary in size ranging from 0.5 to 2.0 µm (79)
(Fig. 1.9). Evidence in support of their role in the transcellular outflow is based on injection of tracer
elements into the anterior chamber with demonstration of the tracers in the vacuoles and pores (80). The
observation that the concentration of tracer material in the giant vacuoles is not always the same as in
the juxtacanalicular connective tissue suggests a dynamic system in which the vacuoles intermittently
open and close to transport aqueous humor from the juxtacanalicular tissue to the Schlemm canal.
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This transcellular transport has active and passive mechanisms. Indirect evidence for active transport
includes the demonstration of enzymes and microscopic structures compatible with an active transport
system in or near the endo — thelial layer (81, 82). However, the bulk of evidence supports the theory of
passive (pressure-dependent) transport, because the number and size of the vacuoles increase with
progressive elevation of the IOP (83). It has been proposed that potential transcellular spaces exist in the
inner wall endothelium of the Schlemm canal, which open as a system of vacuoles and pores, primarily
in response to pressure, to transport aqueous humor from the juxtacanalicular connective tissue to the
Schlemm canal. If intracellular transport through the inner wall endothelium of the Schlemm canal
exists, it has been calculated, on the basis of the estimated size and total number of pores and giant
vacuoles, that resistance to outflow through this system accounts for only a small fraction of the total
resistance to aqueous humor outflow (84). It is also possible that only a portion of the juxtacanalicular
tissue actually filters. It has been suggested that aqueous humor flows preferentially through those
regions of the juxtacanalicular connective tissue nearest the inner wall pores creating a “funneling
effect,” which increases apparent flow resistance in the connective tissue by approximately 30-fold (85).
An alternative theory to that of transcellular transport is paracellular routes between the inner wall
endothelial cells. Perfusion of monkey eyes with cationized ferritin revealed separation of adjacent cell
membranes between tight junctions forming openings and tunnellike channels, which stained with the
tracer indicating intercellular passage (86). These paracellular pathways were larger at higher perfusion
pressure, and apparent giant vacuoles were often dilatations of the paracellular spaces.
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Figure 1.10 Schematic of aqueous humor outflow distal or beyond the “conventional” or trabecular
pathway and into the canal of Schlemm. The canal divides into two or more portions intermittently. The
drawing is divided into four portions by the dotted lines. The internal collector channels of Sondermann
are labeled in the upper right sector as they extend into the trabecular meshwork. The external collector
channels are seen in the upper and lower right sectors, arising from the canal and uniting with the deep
intrascleral plexus of extending directly to the episcleral veins. The deep and intrascleral venous
plexuses are external to the canal. In the upper left sector, an aqueous vein arises from the deep scleral
plexus and another arises from the Schlemm canal and runs directly to the episcleral venous plexus.
External collector veins are seen to arise from the canal and join the deep scleral plexus. In the lower left
sector, the arteries of the deep sclera are seen to be in close relation to the canal of Schlemm. (Modified
from Hogan MA, Alvarado J, Weddell J. Histology of the Human Eye. Philadelphia: WB Saunders;
1971, with permission.)
Of historical interest, the Sondermann canals, although originally described as endothelial-lined
channels communicating between the Schlemm canal and intertrabecular spaces, have subsequently
been interpreted as tortuous communications wandering irregularly and obliquely through the meshwork
(87).
Schlemm Canal
This 360-degree, endothelial-lined channel averages 190 to 370 mm in diameter with occasionally
branching into a plexus-like system (Fig. 1.10) (88). The endothelium of the outer wall is a single cell
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layer that is continuous with the inner wall endothelium but has a smoother surface with larger, less
numerous cells and no pores (89). The outer wall also differs in having numerous, large outlet channels,
which are described below. Smoothmuscle myosin-containing cells have been localized in the human
aqueous humor outflow pathway adjacent to the collector channels, slightly distal to the outer wall of the
Schlemm canal (90). Torus or liplike thickenings have been observed around the openings of the outlet
channels, and septa have been noted to extend from these openings to the inner wall of the Schlemm
canal, which presumably help keep the canal open (88). The endothelium is separated from the
collagenous bundles of the limbus by a basement membrane and fibroblasts (89).
Episcleral and Conjunctival Veins
The Schlemm canal is connected to episcleral and conjunctival veins by a complex system of intrascleral
channels (Fig. 1.10). The aqueous veins of Ascher (91), which are now more commonly referred to as
collector channels (92), have been
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defined as originating at the outer wall of the Schlemm canal and terminating in episcleral and
conjunctival veins in a lamination of aqueous humor and blood, referred to as the laminated vein of
Goldmann. Two systems of intrascleral channels have been identified: (a) a direct system of large
caliber vessels, which run a short intrascleral course and drain directly into the episcleral venous system,
and (b) an indirect system of more numerous, finer channels, which form an intrascleral plexus before
eventually draining into the episcleral venous system (88). The intrascleral aqueous channels do not
connect with vessels of the uveal system, except for occasional fine communications with the ciliary
muscle (93).
The aqueous vessels join the episcleral and conjunctival venous systems by several routes (91). Most
aqueous vessels are directed posteriorly and drain into episcleral veins, whereas a few cross the
subconjunctival tissue and drain into conjunctival veins. Some aqueous vessels proceed anteriorly to the
limbus, with most running a short course parallel to the limbus before turning posteriorly to conjunctival
veins. Casting studies in rabbit and dog eyes revealed a wide venous plexus in the limbic region of the
episcleral vasculature anastomosing with a small arteriolar segment, the latter of which contains smoothmuscle cells that may have a role in regulating aqueous humor drainage by the episcleral venous plexus
and subsequently influencing the IOP (94). In the rhesus monkey, the conjunctival vessels receiving
aqueous humor drainage have a diameter consistent with that of capillaries, whereas most of the vessels
in the episcleral plexus are the size of venules (95). Both types of vessels have simple walls composed
of endothelium and a discontinuous layer of pericytes, through which tracer element (e.g., horseradish
peroxidase) and presumably aqueous humor freely diffuse into subconjunctival and episcleral loose
connective tissue. The episcleral veins drain into the cavernous sinus via the anterior ciliary and superior
ophthalmic veins, whereas the conjunctival veins drain into superior ophthalmic or facial veins via the
palpebral and angular veins (96).
Cellular Organization of the Uveoscleral Pathway
The unconventional outflow for aqueous humor outflow has not been studied as extensively as the
trabecular outflow pathway. Historically, two unconventional pathways have been discriminated: (a)
through the anterior uvea at the iris root, which is referred to the uveoscleral pathway, and (b) through
transfer of fluid into the iris vessels and vortex veins, which has been described as uveovortex outflow.
Uveoscleral Outflow
Tracer studies have shown that aqueous humor passes through the root of the iris and interstitial spaces
of the ciliary muscle to reach the suprachoroidal space (97). From there it passes to episcleral tissue via
scleral pores surrounding ciliary blood vessels and nerves, vessels of optic nerve membranes, or directly
through the collagen substance of the sclera. Studies with cynomolgus monkeys revealed a lower
hydrostatic pressure in the suprachoroidal space than in the anterior chamber, and it was suggested that
this pressure differential is the driving force for uveoscleral outflow (98). The extracellular matrix of
normal human ciliary muscle contains collagen types I, III, and IV; fibronectin; and laminin in
association with muscle fibers and blood vessels, and it has been suggested that the biosynthesis and
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turnover of these glycoproteins may play an important role in resistance to flow within the
unconventional pathways and in mediating the action of certain pharmacologic agents (99). This is
discussed further in the following section on molecular mechanisms of outflow resistance and in Chapter
28 on prostaglandins.
Uveovortex Outflow
Tracer studies in primates have also demonstrated unidirectional flow into the lumen of iris vessel by
vesicular transport, which is not energy dependent (100). The tracer can penetrate vessels of the iris,
ciliary muscle, and anterior choroid to eventually reach the vortex veins; however, the role of net fluid
movement into the iris vasculature is probably clinically insignificant (101). Some evidence suggests
that there is a process of net osmotic resorption of some aqueous humor into the uveal venous
circulation, driven by the high protein content in the blood in these vessels (102). The relative
contribution for this fluid outflow pathway is not understood for the healthy eye, but it may be clinically
relevant in an eye with nanophthalmos (103, 104).
Molecular Mechanisms of Aqueous Humor Outflow Resistance
The biomechanical parameters and fluid hydrodynamics of the aqueous humor outflow pathways are
complex. The technical challenges to study this important scientific discipline include the unique
anatomy of these ocular tissues, the minute amounts of tissue available for study, and the difficulties in
studying these tissues in vivo.
Resistance in the Trabecular Meshwork
Although the precise mechanism of resistance to conventional outflow is unknown, the following
observations provide evidence that most resistance to conventional outflow, or trabecular outflow, is
thought to be a combination of the inner wall endothelial layer and the adjacent juxtacanalicular tissues
(63).
Perfusion Studies
Grant demonstrated that a 360-degree incision of the trabecular meshwork (trabeculotomy) eliminates
approximately 75% of the normal outflow resistance (105). However, when such an eye is perfused at 7
mm Hg, the trabeculotomy eliminates only half the measured aqueous flow resistance (106). The
remainder of the resistance to conventional aqueous humor outflow appears to be within the intrascleral
outflow channels. One study in monkeys has suggested that 60% to 65% of outflow resistance is in the
trabecular meshwork, 25% is in the inner one third to one half of the sclera, and 15% is in the outer one
half to one third of the sclera (107).
Elevating IOP causes an increased resistance to aqueous humor outflow (108, 109), which appears to be
related to a
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collapse of the Schlemm canal due to distention of the trabecular meshwork, an increase in endothelial
vacuoles with ballooning of the inner wall endothelial cells into the canal (83).
As might be expected from these observations, resistance to outflow is decreased by expanding the
Schlemm canal. The trabecular meshwork has been described as a three-dimensional set of diagonally
crossing collagen fibers, which respond to backward, inward displacement with a widening of the
Schlemm canal (110). With either posterior depression of the lens or tension on the choroid (111, 112),
the tension on the trabecular meshwork caused an increased outflow facility, which appeared to be due
to widening of the Schlemm canal and an increase in canal inner wall porosity. Further evidence for the
effect of expanding the Schlemm canal may be supported by the IOP-lowering effect of
viscocanalostomy (113). In contrast, after successful filtration surgery, there is a decrease in the size of
the Schlemm canal, most likely due to underperfusion of the meshwork (114).
The pattern of aqueous humor circulation within the Schlemm canal is not fully understood. Perfusion
studies in enucleated human adult eyes suggest that aqueous humor cannot flow more than 10 degrees
within the canal (211), although there is less resistance to circumferential flow in infant eyes (212).
However, studies of segmental blood reflux into the Schlemm canal imply that the canal is normally
entirely open and that there is circumferential flow (213).
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Other perfusion studies using tracer elements showed relatively free flow through the trabecular spaces
and juxtacanalicular connective tissue until reaching the inner surface of the inner wall endothelium of
the Schlemm canal. However, microspheres of smaller size than those used to determine flow
dimensions in a perfused eye are captured by “sticky wall” interactions (115). This artifact may limit the
information gained from perfusion studies concerning the dimensions of the flowlimiting passages in the
conventional outflow system.
Morphology Changes
The normal human trabecular meshwork undergoes several changes with age. The general configuration
changes from a long, wedge shape (Fig. 1.8) to a shorter, more rhomboidal form (116). The scleral spur
becomes more prominent, the uveal meshwork becomes more compact, and localized closures in the
Schlemm canal are present. The trabecular beams progressively thicken, and the endothelial cellularity
declines at the rate of approximately 0.58% of cells per year, occasionally leading to trabecular
denuding (117, 118). A decrease in the number of giant vacuoles and of the cell count in the Schlemm
canal is explained by an age-related reduction in the size of the Schlemm canal (119). In addition to
these changes, the intertrabecular spaces narrow, and extracellular material increases, especially
electron-dense plaques near the juxtacanalicular tissue that is associated with the ciliary muscle tendons
inserting on the scleral spur (116, 118) with age.
In COAG, there is a marked loss of trabecular meshwork cells leading to fusion and thickening of
trabecular lamellae and a significant increase in electron-dense plaques compared with age-matched
controls owing to components of the extracellular matrix that adhere to the sheaths of the elastic fibers
and their connections to the inner wall endothelium (118). In steroid-induced glaucoma (also discussed
further in the “Glucocorticoid Mechanisms” section), an increase in fine fibrillar material stains for
collagen type IV in the subendothelial region of the Schlemm canal. In pigmentary glaucoma, cell loss is
more prominent than in eyes with COAG presumably due to overload with pigment granules that were
visible in remaining trabecular meshwork cells. The denuded trabecular meshwork areas were collapsed,
and there were areas of disorganized cribriform regions and collapse of the Schlemm canal. These
occluded areas had no pigment granules.
Extracellular Matrix
The extracellular matrix within basement membranes and stroma of the trabecular meshwork plays an
important mechanism for regulating IOP. The extracellular matrix is composed of fibrillar and
nonfibrillar collagens, elastin-containing microfibrils, matricellular and structural organizing proteins,
glycosaminoglycans, and proteoglycans (120). The extracellular matrix of the outflow pathway is
dynamic, undergoing constant turnover and remodeling in response to mechanically induced IOP
stretching through cell adhesion proteins, cell surface receptors, associated binding proteins, certain
cytokines, growth factors, and drugs (121).
The glycosaminoglycans have been extensively studied as a component of the extracellular matrix in the
trabecular meshwork. Recently in an organ culture perfusion study, outflow facility was increased at
least threefold in porcine eyes and 1.5-fold in human eyes by disrupting glycosaminoglycan biosynthesis
with chlorate, an inhibitor of sulfation, and with (ß-xyloside, which provides a competitive nucleation
point for addition of disaccharide units (122). In the control eyes, immunostaining for chondroitin and
heparan sulfates was intensely staining the juxtacanalicular tissue region. In treated eyes, staining was
severely reduced and showed prominent plaques.
Overall in the trabecular meshwork and endothelium of the Schlemm canal, fibrinolysis is favored as a
protective mechanism against obstruction from fibrin and platelets (123). In addition to facilitating the
resolution of fibrin clots, tissue plasminogen activator may also influence resistance to aqueous humor
outflow under normal circumstances by altering the glycoprotein content of the extracellular matrix (84).
Glucocorticoid Mechanisms
The effects of glucocorticoids in the trabecular outflow pathway are complex, with both physiologic and
pharmacologic implications. Glucocorticoids inhibit the synthesis of endogenous prostaglandins (124),
which is clinically relevant because certain prostaglandins increase IOP in high doses but reduce ocular
tension in moderate to low concentrations (see Chapter 28). Glucocorticoid receptors have been
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demonstrated in trabeculectomy specimens from human glaucomatous eyes, nonglaucomatous autopsy
eyes, and cultured human trabecular cells (125, 126). Glucocorticoids may influence the outflow facility
by a direct effect on the extracellular matrix metabolism and the cytoskeleton (127, 128).
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The role of myocilin, previously called TIGR, expression in the trabecular outflow pathways is not fully
understood, but it is clinically important given its role in juvenile glaucoma (see Chapter 8) (129). Some
studies have shown that myocilin expression is increased in trabecular meshwork in response to
dexamethasone (130), but it is curious that patients who have steroid-induced glaucoma do not have
myocilin mutations (131).
Cellular and Cytoskeletal Mechanisms
The trabecular endothelial cells have been shown to phagocytize and degrade foreign material (132); to
phagocytize pigment granules observed in eyes with pigmentary glaucoma (118); and to engulf debris,
detach from the trabecular core, and leave in the Schlemm canal (78). A general mechanism that
contributes to decreased function of trabecular meshwork cells is progressive accumulation of damaged
proteins with age due to oxidative stress and to a decline in the cellular proteolytic machinery that
eliminates misfolded and damaged proteins (133).
Altering trabecular meshwork resistance through the cytoskeleton has been shown in different
experimental models. In a perfusion model with substances that are known to disrupt the microfilaments,
such as cytochalasins, EDTA, or H-7, monkey eyes showed significantly reduced resistance to aqueous
humor outflow, and histology showed alterations in the trabecular meshwork or inner wall of the
Schlemm canal (134). In a perfusion model with sulfhydryl reagents, including iodoacetamide, Nethylmaleimide, and ethacrynic acid, facility of outflow increased owing to an alteration of cell
membrane sulfhydryl groups at multiple sites in the endothelial lining of the Schlemm canal and is not
due to a metabolic inhibition (135, 136, 137 and 138).
Another mechanism by which sulfhydryl groups might modulate aqueous humor outflow involves
hydrogen peroxide, a normal constituent of aqueous humor, which may reduce outflow through
oxidative damage of the trabecular meshwork. Calf trabecular meshwork contains the sulfhydryl
compound, glutathione, as well as the enzyme glutathione peroxidase, which catalyzes the reaction
between glutathione and hydrogen peroxide, thereby detoxifying the latter and presumably protecting
the meshwork from its harmful effects (139). In the pig eye, oxidative damage increases outflow facility
at normal pressure but decreases it with elevated IOP, suggesting that elevated pressure may increase
susceptibility of the outflow pathway to this form of stress (140).
Resistance to Unconventional Outflow
Our understanding of the unconventional outflow system is based more on physiology than on anatomy,
and further study is needed to correlate function and anatomy in this system. In general terms, the
uveoscleral pathway is characterized as “pressure independent,” is reduced by cholinergic agonists
(Chapter 32), decreases with aging, and is enhanced by prostaglandin drugs (Chapter 28) (97). In both
humans and monkeys, there is a decline in uveoscleral outflow with aging (64, 141). A potential
explanation for the observed decline in uveoscleral outflow with aging is thickening of elastic fibers in
the ciliary muscles (141).
Episcleral Venous Pressure
As discussed earlier in this chapter, another factor that contributes to the IOP is episcleral venous
pressure. The precise interrelationship between episcleral venous pressure and aqueous humor dynamics
is complex and is only partially understood. It has been commonly thought that for each mm Hg increase
in episcleral venous pressure the IOP increases one mm Hg, although it may be that the magnitude of
IOP increase is greater than the increase in venous pressure (142). The normal episcleral venous
pressure is reported to be within the range of 8 to 11 mm Hg (143); however, these values are influenced
considerably by the particular technique of measurement (as discussed in Chapter 3).
KEY POINTS
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Our understanding of the embryology of these ocular structures has advanced considerably from
studies in human genetics, cellular and molecular biology, and transgenic animals.
The basic chemistry of the aqueous humor is known. The multiple functions of this dynamic fluid
include maintaining IOP, providing substrates and removing metabolites from the ocular
structures, delivering high concentrations of ascorbate, participating in local paracrine signaling
and immune responses, and providing a colorless and transparent medium as a part of the eye's
optical system.
We have considerable knowledge about the morphology of the ciliary body; however, we do not
yet fully understand the molecular mechanisms that regulate circadian rhythm, hormonal effects,
and aging impact on aqueous humor production.
We have considerable knowledge about the morphology of the trabecular and uveoscleral outflow
pathways in health and aging; however, we do not yet fully understand the molecular mechanisms
that regulate outflow through these pathways. In general, it is thought that most resistance to
outflow is due to a combination of the inner wall endothelial layer and adjacent juxtacanalicular
tissues.
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2 - Intraocular Pressure and Tonometry
> Table of Contents > SECTION I - The Basic Aspects of Glaucoma > 2 - Intraocular Pressure and
Tonometry
2
Intraocular Pressure and Tonometry
INTRAOCULAR PRESSURE What Is Normal?
In individuals who are susceptible to glaucoma, “normal” intraocular pressure (IOP) may be defined as
that pressure which does not lead to glaucomatous damage of the optic nerve head. Unfortunately, such
a definition cannot be expressed in precise numerical terms because individuals show different
susceptibility to optic nerve damage at given pressure levels that also depends on the underlying form of
glaucoma (1, 2). The best we can do is to describe the distribution of IOP in general populations to
establish levels of risk for glaucoma within different pressure ranges. This chapter considers the
distribution of IOP in the general population; the factors, other than glaucoma, that may influence IOP;
and the clinical techniques for measuring IOP. (In Section II, the significance of various pressure levels
in populations of patients with specific types of glaucoma is considered.)
Table 2.1Reported IOP Distributions in General Populations
a
Individuals, n Ages, y
Mean IOP ± SD, mm Hg
Study
MEASURED WITH SCHIÖTZ TONOMETERS
Leydhecker et al., 1958(3)
10,000
10-69
15.8±2.57
Johnson, 1966(14)
7577
>41
15.4 ±2.65
Segal and Skwierczynska, 1967
15,695
>30 15.3-15.9 (range, women) 1967 (15) 15.0-15.2
(15)
(range, men)
MEASURED WITH APPLANATION TONOMETERS
Armaly, 1965(16)
2316
20-79
15.91 ±3.14b
Perkins, 1965(17)
2000
>40
15.2 ±2.5 (OD); 14.9 ±2.5 (OS)
Loewen et al., 1976(18)
4661
9-89
17.18±3.78
Ruprecht et al., 1978(19)
8899
5-94
16.25±3.45
Shiose and Kawase, 1986(20) 75,545 (men); <70;
14.60±2.52;
David et al., 1987(21)
Klein et al., 1992(22)
18,158
(women)
2504
4856
lt;70
15.04±2.33
>40
43-86
14.93±4.04
15.4±3.35
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a Numbers
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in parentheses are reference numbers.
b Computed
from data reported according to sex and age-groups. IOP, intraocular pressure; SD, standard
deviation.
Distribution in General Populations
One of the earliest studies on IOP distribution in the general population was based on Schiötz tonometry
and showed an IOP distribution resembling a Gaussian curve with a skew toward the higher pressures.
In 1958, Leydhecker and associates measured the IOP using Schiötz tonometry in 10,000 individuals
with no known eye disease (3). The mean IOP (± standard deviation [SD]) was 15.5 ± 2.57 mm Hg, and
two SDs above the mean was 20.5 mm Hg, which the authors interpreted as the upper limit of normal
because approximately 95% of the area under a Gaussian curve lies between the mean ± 2 SD.
Subsequent population-based and epidemiologic studies have generally agreed with the findings of
Leydhecker and colleagues, and are summarized in Table 2.1. Initially these results were used to
interpret two subpopulations with a larger “normal” group and a smaller group of “glaucoma” patients
who had higher IOPs (Fig. 2.1). However, we now know that IOP is a causative risk factor for glaucoma
on the basis of evidence
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from clinical trials (4, 5, 6, 7 and 8). We also know that patients with glaucoma show different
susceptibilities for disease progression at given pressure levels and based on the type of glaucoma (2).
Thus, the previous simple notion that a patient's risk for glaucoma could be determined primarily on the
basis of their IOP (Fig. 2.1) is now replaced with our understanding that IOP is a quantitative trait that is
influenced by many factors (9). Although it is readily measured, IOP is a complex trait determined by
aqueous humor flow, uveoscleral outflow, trabecular outflow, and episcleral venous pressure (10, 11,
12, 13, 14 and 15) (see details in Chapter 3).
Figure 2.1 Theoretical distribution of IOPs in nonglaucoma (N) and glaucoma (G) populations, showing
overlap between the two groups. Dotted lines represent uncertainty of extreme values in both
populations.
Factors Affecting IOP
There have been many observations on factors that influence IOP (16, 17, 18, 19, 20, 21, 22 and 23). We
should assimilate these important clinical observations from older studies with the evidence from the
clinical trials, epidemiologic studies, and genetics. In addition, we should anticipate results from future
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studies designed to investigate the complex interactions between genetics and environment. Thus, it may
be helpful to consider how these factors influence IOP on the basis of the categories of genetics,
environment, and physiology.
Genetics
Early family studies provided evidence that IOP can be studied as a quantitative trait (24, 25). In twin
studies, IOP was observed to be more highly correlated between monozygotic than dizygotic twins (26,
27). In addition, the mean IOP showed significantly higher concordance in twin-twin pairs, compared
with twin-spouse pairs (27). Recently, studies have shown that heredity contributes to IOP (28, 29, 30,
31, 32, 33, 34 and 35).
Traditional genetic studies using linkage and genome-wide methods (see Chapter 8) led to the discovery
of several loci, or chromosomal locations, for IOP. In the Blue Mountains Eye Study, commingling
analysis of IOP supported that “a major gene” contributed to the variance of IOP (36). A family study
showed significant linkage for IOP to chromosome 10q22 (37). An affected sibling pair study showed
linkage to chromosomes 5q22 and 14q22 (38). In the Beaver Dam Eye Study, seven loci, on
chromosomes 2, 5, 6, 7, 12, 15, and 19, were reported as being linked to IOP (39). To date, however, no
“IOP genes” have been reported in these chromosomal regions. The next steps will involve validating
and excluding loci, identifying genes in these loci, cross-referencing to databases, and placing these
genes in context with aqueous humor dynamics. It is expected that a combination of genes will be
identified as having major and minor influences on IOP variation and variation in IOP response to
glaucoma medications.
Environment
Thus far, the environmental factors observed to affect IOP may be categorized into physical, smoking,
drug, and dietary exposures. Exposure to cold air reduces IOP, apparently because episcleral venous
pressure is decreased (40). Reduced gravity causes a sudden, marked increase in IOP, apparently
because of cephalad shifts in intravascular and extravascular body fluids (41).
Tobacco smoking causes a transient rise in the IOP immediately after smoking, possibly through a
mechanism of vasoconstriction and elevated episcleral venous pressure (42). However, the direct risk of
tobacco on chronic open-angle glaucoma (COAG) is not evident from epidemiologic and case-control
studies (43, 44).
The impact of various drugs, excluding antiglaucoma drugs (discussed in Section III), are considered in
the general categories of general anesthesia, illicit drugs, and systemic medications. General anesthesia
is usually associated with a reduction in the IOP (45), although some agents used for sedation, such as
ketamine, do not lower IOP (46). The two situations in which the physician must be particularly
concerned about anesthesia-induced alterations in IOP are (a) in the evaluation of infants and children
and (b) in patients who have ocular trauma with a ruptured globe.
In infants and children examined under anesthesia for suspicion of congenital glaucoma, the main
concern is to avoid the artificial reduction of IOP (as discussed earlier), which could mask a pathologic
pressure elevation. In one study, the mean (± SD) IOP for children measured under halothane anesthesia
was 7.8 ± 0.4 mm Hg at age 1 year, with a gradual increase of about 1 mm Hg per year of age to 11.7 ±
0.6 mm Hg at age 5 years (47).
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When operating on an open eye, such as after penetrating injury or during intraocular surgery, the
primary concern is to avoid sudden elevations of IOP that might lead to extrusion of ocular contents.
Depolarizing muscle relaxants, such as succinylcholine and suxamethonium, cause a transient increase
in IOP, possibly because of a combination of extraocular muscle contraction and intraocular vasodilation
(45). In comparing intubation methods, the laryngeal mask airway causes less of an IOP risk, compared
with tracheal intubation, and has the added advantage of less postintubation coughing and other
symptoms (48, 49).
Among the illicit drugs, heroin and marijuana lower the IOP (the latter is discussed further in Section
III), whereas LSD (lysergic acid diethylamide) elevates the IOP (50, 51).
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Among the many systemic medications that may potentially affect IOP, the most relevant for clinical
consideration include corticosteroids, anticholinergic agents, and unusual reaction to sulfonamides.
Given the use of corticosteroids systemically for immunosuppression and dramatic increased intraocular
use to treat retinal diseases, the potential risk of IOP elevation and steroid-induced glaucoma should be
monitored in a patient receiving such treatment (see Chapter 23).
In general, the labels on systemic anticholinergics, antihistamines, decongestants, and psychiatric
medications having some anticholinergic effects state warnings such as “contraindicated in patients with
glaucoma.” These warnings are meant to alert the patient and prescribing physician that use of these
medications can precipitate pupillary block glaucoma or acute angle-closure glaucoma in patients with
anatomically narrow angles (see Chapter 12) (52). Cases of acute angle-closure glaucoma have been
reported with the use of scopolamine dermal patches for motion sickness, and the use of aerosolized
atropine and ipratropium for chronic obstructive pulmonary disease (53, 54 and 55). However, in
patients with COAG, scopolamine was shown not to affect IOP (56). It would be expected that these
other agents would not elevate IOP in patients with COAG.
The potential effects of dietary exposures on IOP have not been studied extensively (57). Acute doses of
alcohol lower IOP, but the mechanism is not associated with a change in facility of aqueous outflow
(58). The mechanism may be a combination of suppressed circulating antidiuretic hormone, leading to a
reduction of net water movement into the eye, and direct inhibition of aqueous secretion (59). However,
the clinical relevance of this acute effect is unknown since recent epidemiologic studies have not shown
that alcohol consumption affects IOP or the risk for glaucoma (60, 61 and 62).
Caffeine consumption may cause a slight, transient rise in IOP, although the levels associated with
customary coffee drinking do not appear to cause a significant, sustained pressure elevation (63). There
does not appear to be an overall population-based associated risk for glaucoma with caffeine
consumption (64).
Recent epidemiologic studies have used validated nutritional surveys to analyze the association between
certain dietary exposures and risk of COAG. In the Nurses' Health Study (with 76,200 respondents) and
the Health Professionals Follow-up Study (40,284 participants), no strong association was found
between antioxidant consumption and the risk of COAG (65). According to a women's health study of
1155 participants, a higher intake of certain fruits and vegetables may be associated with as much as a
69%-decreased risk of glaucoma (66). In a study comparing diets with sufficient and deficient intakes of
omega-3 fatty acids since conception, those rats fed a sufficient omega-3 diet had decreased IOP with
increasing age because of increased outflow facility, likely resulting from an increase in docosanoids
(67).
Physiology
Sex
Overall, sex appears to have no major effect on IOP in the 20- to 40-year age-group. In older agegroups, the apparent rise in mean IOP with increasing age is greater among women than men, and
coincides with the onset of menopause, whereas the increase in the standard deviation of the IOP
distribution is equal between men and women in white populations (16, 22). In a population-based
Japanese study, IOP did not differ between women and men (68). In the Barbados Eye Study, which had
a mixed population of participants, IOP was higher among women than men (69).
Age
IOP generally increases with age. Studies indicate that children have significantly lower pressures than
adults do, although tonometric measurements may be influenced by the level of cooperation of the child
if he or she is awake, the type of tonometer used to measure the IOP, and the general anesthetic when
the child is asleep or sedated (47, 70) (discussed earlier, under “Environment”).
The reported mean (± SD) IOP, by using only topical anesthesia for the tonometry, is 11.4 + 2.4 mm Hg
in newborns and 8.4 + 0.6 mm Hg in infants younger than 4 months of age (47, 71). In a study of 460
children between birth and 16 years of age using a noncontact tonometer, the mean IOP increased from
9.59 + 2.3 mm Hg at birth to 13.73 + 2.05 mm Hg at 3 to 4 years, with more stable measurements
obtained thereafter (72). In another study, of 405 children between birth and 12 years, using the Perkins
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applanation tonometer, the mean IOP was 12.02 + 3.74 mm Hg (73). In this pediatric cohort, IOP
showed a trend of increasing IOP with age (correlation coefficient [r] =0.49) that approached adult IOP
levels by 12 years of age; also observed were increased IOP with hyperopia (r = 0.69) and corneal
thickness measured by pachymetry (r = 0.39). IOP was inversely proportional to axial length (r = -0.1).
Results of studies in premature infants have been conflicting, with mean IOPs of 18 mm Hg in one study
and 10.13 to 10.17 mm Hg in another (74, 75). The tonometer may also influence the results, with mean
IOP measurements in 50 supine children younger than 5 years of 5.89 mm Hg with a handheld
applanation tonometer and 14.76 mm Hg with a pneumotonometer (76). In a study of 77 children (132
eyes; mean age, 1 year, 7 months; range, 1 month to 60 months), mainly with retinopathy of prematurity
(107 eyes), IOP was measured by using the Perkins, Schiötz, and Tono-Pen tonometers (70).
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There was no significant difference between the mean IOPs obtained with the Tono-Pen and the Perkins,
but the Schiötz measurements were significantly higher than those obtained with the Perkins and TonoPen tonometers.
In adults, the IOP distribution is Gaussian between 20 and 40 years of age (16), but tends to increase
with advancing age (22). A study of 69,643 Japanese participants suggested that study design may
influence the findings, in that a cross-sectional analysis showed a significant decrease in IOP with age,
whereas a longitudinal analysis showed a significant increase (77). In a Malay Singapore cohort, IOP
increased with age to the sixth decade, but with further increase in age there was a decrease in IOP,
resulting in an inverted-U distribution pattern (78). Regression analysis showed that age, central cornea
thickness (CCT), and systolic blood pressure were significant determinants of IOP in persons aged 40 to
80 years; CCT was a more important determinant in younger persons. In the white cohort of the Beaver
Dam Eye Study, a population-based study of agerelated eye diseases in persons aged 43 to 86 years,
significant physiologic covariates on IOP with aging included systolic and diastolic blood pressures,
body mass index, hematocrit, serum glucose, glycohemoglobin, cholesterol level, pulse, nuclear
sclerosis, season, and time of day of the measurement (22).
In terms of aging effects on aqueous humor dynamics, studies have shown that there is reduced facility
of aqueous outflow and uveoscleral outflow, and a decrease in aqueous production (79, 80 and 81).
Episcleral venous pressure does not appear to change significantly with advancing age (80, 82).
Ethnicity
Clinical trials and population-based studies have shown that there is an increased risk for COAG among
blacks, and for angle-closure glaucoma in certain Asian populations (83, 84 and 85). However, with the
current understanding of IOP as a causative risk factor for glaucoma and that a thin central cornea
confers an increased risk for COAG, recent studies using regression analysis of multiple covariates
found that black race is not an independent risk factor, although black individuals tend to have thinner
corneas, greater cup-to-disc ratios, and higher IOP, which increase their risk (86). As we learn more
about the biological and genomic correlates of the clinical risk factors for glaucoma, we will understand
the basis of the earlier clinical observations of ethnoracial-based risk for glaucoma.
Refractive Error
In the infant eye, elevated IOP causes axial myopia as evident by buphthalmos (discussed further in
Chapter 13). In older children, a positive correlation between IOP and both axial length of the globe and
increasing degrees of myopia has been reported (21, 87, 88 and 89). Increasing IOP was also related to
myopia in a study of 321 children (mean age, 9.8 years) (90). However, more recent studies have found
no correlation between higher IOP and myopia in children (91, 92).
In adults, it is still not known whether myopia is a risk factor for COAG. Some epidemiologic studies
show no association (93), whereas other studies report a positive association between myopia and
COAG (94, 95 and 96). In the studies reporting an association between myopia and COAG, it is hard to
know whether the higher pressures in this group reflect early glaucoma cases or a truly higher IOP
distribution throughout the myopic population.
Diurnal and Postural Variation
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Like many biological parameters, the IOP is subject to cyclic fluctuations throughout the day (97, 98 and
99). In a study of 1062 persons middle-aged and older, the IOP was highest during the daytime (100). A
study of 690 diurnal curves found that IOP peaked in the early morning for 40% of patients, and before
noon in 65% (101). In a study of persons in China with (N = 59) and without (N = 67) ocular
hypertension, IOP was highest in the morning (102).
More recent studies have taken into account postural variation in IOP and showed consistent elevation
of IOP at nighttime (97, 103), which is physiologically relevant because sleep occurs in the supine
position. Whole-body, head-down tilt leads to a further increase in IOP, which correlates with the degree
of inversion, is greater in glaucomatous eyes, and appears to be related to elevated episcleral venous
pressure (104, 105 and 106). Thus, obtaining clinical history on type of exercise—in particular, yoga
and inversion—may be relevant for the patient with glaucoma. However, it is still unknown whether
IOP changes induced by position contribute to optic nerve damage.
The obvious primary clinical value of measuring diurnal IOP variation is to avoid missing a pressure
elevation with single readings; however, diurnal measurement is impractical in a busy clinical practice,
and the logistics of obtaining the diurnal measurements is a practical concern. In any case, many
physicians use a modified diurnal curve, by measuring the IOP in the office approximately every 2 hours
from early morning to late afternoon or early evening. It has been suggested that measuring IOP in
supine position during office hours estimates peak nocturnal IOP better than sitting measurements do
(107).
In addition to trying to detect maximum IOP data as a risk for glaucoma, detecting large IOP
fluctuations is also important. In a study of 64 patients with COAG and documented IOP less than 25
mm Hg over a mean follow-up of 5 years, patients were trained to perform 5 days of home selftonometry (described later in this chapter) (108). Although mean home IOP and baseline office IOP
were similar (16.4 ±3.6 mm Hg and 17.6 ± 3.2 mm Hg, respectively), the diurnal IOP range and the IOP
range over multiple days were significant risk factors for progression. The risk for visual field
progression within 8 years among patients with a diurnal IOP range of 5.4 mm Hg was nearly six times
as high as that among patients with IOP fluctuation of 3.1 mm Hg. Baseline office IOP had no predictive
value.
The physiologic mechanisms that regulate diurnal IOP variation are complex. The IOP is regulated in
part by adrenocortical steroids and catecholamines (109, 110 and 111). The circadian rhythm of aqueous
flow also does not appear to be influenced by plasma melatonin levels (112). In terms of circadian
rhythm and the four parameters of aqueous humor dynamics, the reproducible circadian rhythm of
higher aqueous humor flow in the morning compared with night does not solely explain the diurnal IOP
variation (98, 113, 114).
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Exertional Influences
Straining, as associated with the Valsalva maneuver, electroshock therapy, or playing a high-resistance
musical instrument, has been reported to elevate the IOP (115, 116 and 117). The mechanisms include
elevated episcleral venous pressure, especially with the Valsalva maneuver; uveal engorgement; and
possibly, increased orbicularis tone. Of particular clinical relevance is that overweight patients may have
artificial IOP elevations when measured with Goldmann applanation tonometry, because they strain to
reach the instrument; this can be overcome by measuring the pressure with the patient in a relaxed
position, by using a Perkins tonometer (118).
Exercise has been shown to lower IOP in persons with and without glaucoma (119). The effect of
aerobic exercise on IOP lowering is observed in patients receiving topical glaucoma medication (120).
There is clinical relevance for taking an exercise history. For instance, in young patients with advanced
congenital or juvenile glaucoma, exercise-induced decrease in central visual acuity and reduced foveal
sensitivity on perimetry may occur transiently during exercise (121). Another example is that some
patients with pigmentary dispersion syndrome or pigmentary glaucoma develop exercise-induced
anterior chamber pigment dispersion with IOP elevation, which can be minimized with the use of low-
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dose pilocarpine before exercise (122); pilocarpine causes miosis, minimizing the contact between the
midperipheral iris and zonules (see Chapter 31).
Several theories on mechanisms for exercise-induced IOP reduction have been investigated and include
metabolic acidosis, and hypocapnia and blood lactate levels; exercise-induced IOP changes do not
appear to be related to hydration status and other serology parameters, such as plasma osmolality (123,
124 and 125). Clearly, the mechanisms involved in exercise-induced IOP reduction are complex and
may differ between sedentary and conditioned patients, and between young and older patients.
Regardless, future research should incorporate health behaviors that include nutritional intake, body
mass index and obesity, exercise, smoking, and sleep apnea (126).
Eyelid and Eye Movement
Blinking has been shown to raise the IOP by 10 mm Hg, and hard eyelid squeezing may raise it to as
high as 90 mm Hg (127). Voluntary eyelid fissure widening causes an increase in IOP of about 2 mm
Hg, which may relate to an increased orbital volume from retraction of the upper eyelid into the orbit
(128). Contraction of extraocular muscles also influences the IOP. There is an increase in IOP on upgaze in healthy individuals, which is augmented by Graves infiltrative ophthalmopathy (129). During
strabismus surgery, especially for eyes with thyroid ophthalmopathy, the IOP has been recorded to
increase to as high as 84 mm Hg (130).
Intraocular Conditions
Some intraocular conditions may lead to a reduction in IOP. In the clinical setting of anterior uveitis
without angle abnormalities, IOP may be reduced slightly. It has traditionally been thought that this is
because of a decrease in aqueous humor formation (131), although anterior segment inflammation has
also been shown to increase uveoscleral outflow in monkeys by reducing the density of collagen type I
in the extracellular matrix of the ciliary body (132). Rhegmatogenous retinal detachment may also be
associated with a reduced IOP, apparently because of reduced aqueous flow, as well as a shunting of
aqueous from the posterior chamber, through the vitreous and retinal hole, into the subretinal space, and
across the retinal pigment epithelium (131).
Systemic Conditions
On the basis of public health relevance, the two most common systemic diseases studied for potential
contributory risk for glaucoma are hypertension and diabetes mellitus. The more recent epidemiology
studies find a positive correlation between systemic hypertension and IOP in Latinos, Japanese, aging
men, persons of mixed African descent, the Blue Mountains Eye Study cohort, and whites in the Beaver
Dam Eye Study (88, 99, 133, 134, 135 and 136). In contrast, hypertension was not associated with
glaucoma risk in Asian Indians (137). Retinal microvascular abnormalities seen with hypertension were
not associated with risk for glaucoma among white participants in the Beaver Dam Eye Study (138). The
mechanisms responsible for hypertension and risk for elevated IOP and glaucoma may involve a
combination of ocular pulse pressure and ocular perfusion pressure (8, 139, 140).
The potential influence of diabetes on IOP and glaucoma risk is unclear on the basis of epidemiology,
clinical trials, and large clinical studies. In a population-based study in 3280 Malay adults aged 40 to 80
years, diabetes and metabolic abnormalities were associated with a small increase in IOP but were not
significant risk factors for glaucomatous optic neuropathy (141). In the Latino cohort of the Los Angeles
Latino Eye Study, presence of type 2 diabetes and a longer duration of diabetes were independently
associated with an increased risk for COAG (142). In a black cohort of African ancestry, diabetes was
associated with increased IOP (134). In the Rotterdam Study and among an Asian Indian population,
diabetes was not a risk factor for COAG (137, 143).
An earlier study in dogs reported that retrolaminar pressure (i.e., pressure surrounding the optic nerve
subarachnoid space) was lower, but dependent on cerebrospinal fluid (CSF) pressure (144). The
investigators stated that the translaminar pressure gradient across the lamina cribrosa varied
independently of IOP, and they hypothesized that this maybe important in the pathophysiology of
glaucoma. Subsequent clinical studies support this hypothesis. In a case-control study involving patients
who had a lumbar puncture, the opening CSF pressure in 28 patients with COAG was 9.2 ±2.9 mm Hg,
which was significantly lower than that of the 49 controls, in whom the pressure was 13.0 ± 4.2 mm Hg
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(145). Another case-control study showed a glaucoma prevalence of 18.1% in patients with normalpressure hydrocephalus and 5.6% in controls with hydrocephalus (146). In a prospective study, CSF
pressure was lower in patients with COAG than in persons without COAG, and was lower among
patients with normal-tension glaucoma than among those with high-pressure glaucoma (147).
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Obesity and body mass index have also been associated with increased IOP (20, 22, 68, 148). However,
the relationship between obesity and increased body mass index and risk of glaucoma is not understood
(149). In Graves disease, increased rate of ocular hypertension has been reported in several studies (150,
151, 152 and 153), and one study reported that such patients have normal corneal thickness (154).
Although it is logical to hypothesize that thyroid hormone has some influence on IOP, the mechanism of
this hormone on aqueous humor dynamics has not been elucidated (155, 156).
Some case series and case-control studies have shown an increased rate of COAG in patients with sleep
apnea (157, 158). In myotonic dystrophy, the IOP is markedly low, which not only may be partially due
to reduced aqueous production but also may be due to increased outflow, possibly by the uveoscleral
route from atrophy of the ciliary muscles (159, 160). Hyperthermia has been shown to cause an
increased IOP (161). Patients with human immunodeficiency virus (HIV) have a relatively low mean
IOP, which correlates with low CD4+ T-lymphocyte counts and the presence and extent of
cytomegalovirus retinitis (162).
TONOMETERS AND TONOMETRY
Classification of Tonometers
All clinical tonometers measure the IOP by relating a deformation of the globe to the force responsible
for the deformation (163). The two basic types of tonometers differ according to the shape of the
deformation: indentation and applanation (flattening).
Indentation Tonometers
The shape of the deformation with this type of tonometer is a truncated cone (Fig. 2.2A). The precise
shape, however, is variable and unpredictable. In addition, these instruments displace a relatively large
intraocular volume. As a result of these characteristics, conversion tables based on empirical data from
in vitro and in vivo studies must be used to estimate the IOP. The prototype of this group, the Schiötz
tonometer, was introduced in 1905.
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Figure 2.2 Corneal deformation created by (A) indentation tonometers (a truncated cone) and (B)
applanation tonometers (simple flattening).
Applanation Tonometers
The shape of the deformation with these tonometers is a simple flattening (Fig. 2.2B), and because the
shape is constant, its relationship to the IOP can, in most cases, be derived from mathematical
calculations. The applanation tonometers are further differentiated on the basis of the variable that is
measured.
Variable Force
This type of tonometer measures the force that is required to applanate (flatten) a standard area of the
corneal surface. The prototype is the Goldmann applanation tonometer, which was introduced in 1954.
Variable Area
Other applanation tonometers measure the area of the cornea that is flattened by a known force (weight)
(Table 2.2). The prototype in this group is the Maklakoff tonometer, which was introduced in 1885. The
division between indentation and applanation tonometers, however, does not correlate entirely with the
magnitude of intraocular volume displacement. Goldmanntype tonometers have relatively minimal
displacement, whereas that with Maklakoff-type tonometers is sufficiently large to require the use of
conversion tables.
Noncontact Tonometer
A third type of tonometer uses a puff of air to deform the cornea and measures the time or force of the
air puff that is required to create a standard amount of corneal deformation. The prototype was
introduced by Grolman in 1972.
Table 2.2Applanation Tonometers with Variable Area
Tonometer
Description/Use
Maklakoff-Kalfa
Prototype
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Applanometer
Tonomat
Halberg tonometer
Barraquer tonometer
Ocular tension
indicator
Glaucotest
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Ceramic endplates
Disposable endplates
Transparent endplate for direct reading: multiple weights
Plastic tonometer for use in operating room
Uses Goldmann biprism and standard weight, for screening (measures above or
below 21 mm Hg)
Screening tonometer with multiple endplates for selecting different “cutoff”
pressures
Figure 2.3 A: The Imbert-Fick law (W=PtxA). B: Modification of Imbert-Fick law for the cornea (W+S
= PtxA1+B).
Next, we describe these various tonometers and their techniques, and compare their relative values and
limitations.
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Goldmann Applanation Tonometry
Basic Concept
Goldmann based his concept of tonometry on a modification of the Maklakoff-Fick law, also referred to
as the Imbert-Fick law (164). This law states that an external force (W) against a sphere equals the
pressure in the sphere (Pt) multiplied by the area flattened (applanated) by the external force (A) (Fig.
2.3A):
W=PtX A
The validity of the law requires that the sphere be (a) perfectly spherical, (b) dry, (c) perfectly flexible,
and (d) infinitely thin. The cornea fails to satisfy any of these requirements, in that it is aspherical and
wet, and neither perfectly flexible nor infinitely thin. The moisture creates a surface tension (S), and the
lack of flexibility requires a force to bend the cornea (B), which is independent of the internal pressure.
In addition, because the cornea has a central thickness of approximately 550 µm, the outer area of
flattening (A) is not the same as the inner area (A1). It was, therefore, necessary to modify the ImbertFick law in the following manner to account for these characteristics of the cornea (Fig. 2.3B):
W+S = PtA1 + B
When A1 equals 7.35 mm2, S balances B and W equals Pt. This internal area of applanation is obtained
when the diameter of the external area of corneal applanation is 3.06 mm, which is used in the standard
instrument. The volume of displacement produced by applanating an area with a diameter of 3.06 mm is
approximately 0.50 mm3, so that Pt is very close to P0, and ocular rigidity does not significantly
influence the measurement.
Description of Tonometer
The instrument is mounted on a standard slitlamp in such a way that the examiner's view is directed
through the center of a plastic biprism, which is used to applanate the cornea. Two beam-splitting prisms
within the applanating unit optically convert the circular area of corneal contact into semicircles. The
prisms are adjusted so that the inner margins of the semicircles overlap when 3.06 mm of cornea is
applanated. The biprism is attached by a rod to a housing, which contains a coil spring and series of
levers that are used to adjust the force of the biprism against the cornea (Fig. 2.4).
Technique
The cornea is anesthetized with a topical preparation, and the tear film is stained with sodium
fluorescein. With the cornea and biprism illuminated by a cobalt blue light from the slitlamp, the biprism
is brought into gentle contact with the apex of the cornea (Fig. 2.5). The fluorescence of the stained tears
facilitates visualization of the tear meniscus at the margin of contact between cornea and biprism. The
fluorescent semicircles are viewed through the biprism, and the force against the cornea is adjusted until
the inner edges overlap (Fig. 2.6). The influence of the ocular pulsations is seen when the instrument is
properly positioned, and the excursions must be averaged to give the desired endpoint. The IOP is then
read directly from a scale on the tonometer housing.
The staining of the tear film may be accomplished by instilling a drop of topical anesthetic and touching
a fluoresceinimpregnated paper strip to the tears in the lower cul-de-sac or using a commercial
fluorescein solution combined with a topical anesthetic. With the commercial preparations, there is
potential concern with bacterial contamination (165). When contaminated with Pseudomonas or
Staphylococcus, a fluorescein preparation with the anesthetic, benoxinate, and the preservative,
chlorobutanol (Fluress), regained sterility in the solution in 1 minute and on the dropper tip in 5 minutes,
whereas sterility in preparations with proparacaine and thimerosal took at least 1 hour (166).
Sources of Error with Goldmann Tonometry
Tonometry has potential sources of error (167). The appropriate amount of fluorescein is important
because the width of the semicircle meniscus influences the reading. Wider menisci cause falsely higher
pressure estimates. Improper vertical alignment (one semicircle larger than the other) will also lead to a
falsely high IOP estimate (Fig. 2.6).
The mathematical calculation for Goldmann applanation tonometry is based on a presumed average
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CCT of 520 µm. Deviations from the average CCT are a source of error with cornea edema
underestimating the true IOP, whereas variations of CCT in normal corneas can lead to falsely higher
pressure readings with thicker corneas and falsely lower ones with thinner corneas (168). After
refractive surgery, the IOP is lower due
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to a thinner cornea as a result of laser-assisted in situ keratomileusis (LASIK) (169).
Figure 2.4 Goldmann-type applanation tonometry. A: Basic features of tonometer, shown in contact with
patient's cornea. B: Enlargement shows tear film meniscus created by contact of biprism and cornea. C:
View through biprism (1) reveals circular meniscus (2), which is converted into semicircles (3) by
prisms.
These latter observations have been evaluated to address the variance of CCTs in general populations
and subgroups, including various glaucoma groups and the effect of refractive surgery influence the IOP
measurements (170). From 300 datasets involving healthy eyes, the group-averaged CCT was 534 µm.
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From 230 datasets in which interindividual variance was reported, the group-averaged CCT (±SD) was
536 + 31 µm. There are ethnoracial differences, with thinner mean CCTs of 530 to 531 µm in one
African-American population and 495 to 514 µm in a Mongolian population (171, 172). A study in
Japan revealed a mean of 552µm among healthy persons (173). Individuals in the Ocular Hypertension
Treatment Study (OHTS) had a mean CCT of 573.0 ± 39.0 µm, and 24% of the OHTS cohort had a
CCT greater than 600 µm (174). Patients with normal-tension glaucoma have thinner mean CCTs of 514
to 521 µm(175).
Figure 2.5 Technique of applanation tonometry with Goldmann tonometer.
This variance of CCT and its effect on the accuracy of IOP measurements raised questions as to what
correction factor for the adjusted IOP measurement should be used when the CCT deviates from the
assumed average, 520 µm. Ehlers and colleagues have published a table in which the average error is 0.7
mm Hgper 10 µ of deviation from the mean of 520 µ (168). Another study, however, revealed a smaller
error, of 0.19 mm Hg per 10 µ (176), which is consistent with findings of a direct cannulation study
(177). IOP measurements with the Tono-Pen are also affected by CCT, with reported errors of 0.29 mm
Hg per
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10 µ in men and 0.12 mm Hg per 10 µ in women (178). However, there is a lack of general agreement
on the correction factor that should be used for adjusting the IOP measured by Goldmann tonometry,
when the CCT deviates from the norm (179).
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Figure 2.6 Semicircles of Goldmann-type applanation tonometry. A: Slitlamp view of Goldmann mires.
B: Proper width and position. Enlargement (B, at right) depicts excursions of semicircles caused by
ocular pulsations. C: Semicircles are too wide. D: Improper vertical and horizontal alignment.
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Deviations of corneal curvature also influence IOP measurements, with an increase of approximately 1
mm Hg for every 3 diopters (D) of increase in corneal power (180). Marked corneal astigmatism
produces an elliptical area of corneal contact. When the biprism is in the usual orientation, with the
mires displaced horizontally, the IOP is underestimated for with-therule and overestimated for againstthe-rule astigmatism, with approximately 1 mm Hg of error for every 4 D of astigmatism (181). To
minimize this error, the biprism may be rotated until the dividing line between the prisms is 45 degrees
to the major axis of the ellipse, or an average may be taken of horizontal and vertical readings. An
irregular cornea distorts the semicircles and interferes with the accuracy of the IOP estimates.
Prolonged contact of the biprism with the cornea leads to corneal injury, as manifested by staining,
which makes multiple readings unsatisfactory. In addition, prolonged contact causes a decrease in IOP
over a period of minutes, which is less pronounced in eyes with carotid occlusive disease, suggesting
that it may be related to intraocular blood (182).
The Goldmann tonometer must be calibrated at least monthly. Instructions for quick, simple calibration
come with the instrument. If the tonometer does not meet calibration specifications, it must be returned
to the manufacturer or distributor for recalibration or repair.
Disinfection of Goldmann (and Other) Tonometers
With all tonometers that contact the eye, there is the risk of transmitting infection, such as the
adenovirus of epidemic keratoconjunctivitis and herpes simplex virus type 1. In addition, there is the
potential for transmitting more serious diseases, such as hepatitis and acquired immunodeficiency
syndrome (AIDS) (183, 184), although there is no evidence to suggest transmission of HIV by contact
with tears.
Various techniques have been described for disinfecting tonometer tips (185, 186). Adenovirus type 8
was removed or inactivated by soaking the applanation tip for 5 to 15 minutes in diluted sodium
hypochlorite (1:10 household bleach), 3% hydrogen peroxide, or 70% isopropyl alcohol, or by wiping
with alcohol, hydrogen peroxide, iodophor (povidone-iodine), or 1:1000 Merthiolate (187). Herpes
simplex virus type 1 was eliminated by swabbing the applanation head with 70% isopropyl alcohol
(188). Ten minutes of continuous rinsing in running tap water was reported to remove all detectable
hepatitis B virus (HBV) surface antigen from contaminated tonometers (183), although another study
showed that soap-and-water wash was the only disinfection method that removed all HBV DNA (189).
Wiping with 3% hydrogen peroxide or 70% isopropyl alcohol swabs completely disinfected tonometer
tips contaminated with HIV-1 (190).
The American Academy of Ophthalmology Clinical statement on infection prevention in eye care
services and operating areas and operating rooms
(http://one.aao.org/CE/PracticeGuidelines/ClinicalStatements_Content.aspx?cid=bfa87dce-adc9-445094a2-e49493154238) references the guidelines of the U.S. Centers for Disease Control and Prevention
(186). With any technique, it is important to carefully remove the disinfectant from the contact surface
before the next use, because alcohol and hydrogen peroxide each cause transient corneal defects.
Other Applanation Tonometers with Variable Force
The Maklakoff applanation tonometer was once popular in Russia and consisted of a dumbbell-shaped
metal cylinder; it had a 10-mm diameter flat endplate of polished glass on either
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end. A set of four such instruments were available, weighing 5, 7.5, 10, and 15 g. A dye suspension of
Argyrol, glycerin, and water was applied to either endplate and, with the patient in a supine position and
the cornea anesthetized, the instrument rested vertically on the cornea for 1 second. The resultant
circular white imprint on the endplate corresponded to the area of cornea that was flattened. The
diameter of the white area is measured with a transparent plastic measuring scale to 0.1 mm, and the IOP
is read from a conversion table in the column corresponding to the weight used (191).
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Figure 2.7 Applanation tonometry using the Perkins tonometer.
Although not commonly used now, the Perkins applanation tonometer uses the same biprism as the
Goldmann applanation tonometer (192). The light source is powered by a battery and the force is varied
manually. A counter balance makes it possible to use the instrument in either the vertical or horizontal
position (Fig. 2.7). The Draeger applanation tonometer is similar to the Perkins tonometer, but uses a
different biprism and has an electric motor that varies the force (193).
The original Mackay-Marg tonometer, which is no longer available, had a plate diameter of 1.5 mm
surrounded by a rubber sleeve. The force required to keep the plate flush with the sleeve was
electronically monitored and recorded on a paper strip (194). The most commonly used Mackay-Margtype tonometer today is the Tono-Pen, a handheld instrument with a strain gauge that creates an
electrical signal as the footplate flattens the cornea (195) (Fig. 2.8). A built-in single-chip
microprocessor senses the proper force curves and averages 4 to 10 readings to give a final digital
readout. It also provides the percentage of variability between the lowest and highest acceptable
readings from 5% to 20%.
The pneumotonometer is similar to the Mackay-Marg in that a central sensing device measures the IOP,
while the force required to bend the cornea is transferred to a surrounding structure. The sensor in this
case, however, is air pressure, rather than an electronically controlled plunger (196). At one end of a
pencil-like holder is a sensing nozzle, which has a 0.25-inch outer diameter and a 2.0-mm central
chamber. The nozzle is covered with a Silastic diaphragm, and pressurized air in the central chamber
exhausts at the face of the nozzle between the orifice of the central chamber and the diaphragm. As the
sensing nozzle touches the cornea and when the area of contact equals that of the central chamber, an
initial inflection is recorded, which represents the IOP and the force required to bend the cornea (Fig.
2.9). With further enlargement of the corneal contact, the bending force is transferred to the face of the
nozzle, which is interpreted as the actual IOP.
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Figure 2.8 Technique of measuring IOP with handheld Tono-Pen.
A newer applanation tonometer with a disposable cover, called the PASCAL tonometer, is available
(Fig. 2.10). It repeatedly samples IOP 100 times per second in addition to ocular pulse amplitude and the
systemic pulse rate (197). This portable slitlamp mounted device provides a digital output of the IOP
and a graphic output of the ocular pressure pulse.
The noncontact tonometer was introduced by Grolman (198) and has the advantage over other
tonometers of not touching the eye, other than with a puff of air. This instrument should not be confused
with the pneumatic tonometers discussed earlier that require eye contact. After proper alignment of the
patient, a puff of room air creates a constant force that momentarily deforms the central cornea, which is
detected by an optoelectronic system of a transmitter, which directs a
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collimated beam of light at the corneal vertex, and a receiver and detector, which accepts only parallel,
coaxial rays reflected from the cornea. At the moment that the central cornea is flattened, the greatest
number of reflected light rays are received, which is recorded as the peak intensity of light detected. The
time from an internal reference point to the moment of maximum light detection is converted to IOP.
With the newer instrument, additional data is provided on cornea hysteresis, which may be an indication
of elasticity (199). The time interval for an average noncontact tonometer measurement is 1 to 3
milliseconds (1/500th of the cardiac cycle) and is random with respect to the phase of the cardiac cycle
so that the ocular pulse becomes a significant variable—that is, unlike with some tonometers, it cannot
be averaged. The probability that an instantaneous pressure measurement will lie within a given range of
mean IOP increases as the number of tonometric measurements, averaged together, increases (200). For
this reason, it is recommended that a minimum of three readings within 3 mm Hg be taken and averaged
as the IOP.
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Figure 2.9 IOP measurement using a pneumotonometer.
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Figure 2.10 Measurement of IOP using the Pascal Dynamic Contour Tonometer.
Schiötz Indentation Tonometry
The prototype indentation tonometer is the Schiötz tonometer, which consists of a footplate that rests on
the cornea and a weighted plunger that moves freely (except for the effect of friction) within a shaft in
the footplate with the degree to which it indents the cornea is indicated by the movement of a needle on
a scale. A 5.5-g weight is permanently fixed to the plunger, which can be increased to 7.5,10, or 15 g by
adding additional weights (Fig. 2.11). When the plunger indents the cornea, the baseline or resting
pressure (P0) is artificially raised to a new value (Pt). The change in pressure from P0 to Ptis an
expression of the resistance an eye offers to the displacement of a volume of fluid (Vc). Because the
tonometer actually measures Pt, it is necessary to estimate P0 for each scale reading and weight. Schiötz
estimated P0 by experiments in which a manometer was attached to enucleated eyes by a cannula
inserted through the optic nerve.
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Figure 2.11 Technique of IOP measurement using Schiötz indentation tonometer.
In the early days of indentation tonometry, the IOP values that were considered to be normal were
considerably higher than today's accepted range, and it was not until Friedenwald's work that indentation
tonometry acquired a mathematical basis (201). The formula has a single numerical constant, the
coefficient of ocular rigidity (K), which is roughly an expression of the distensibility of the eye. He
developed a nomogram for estimating K on the basis of two tonometric readings with different weights,
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and subsequent studies using applanation tonometry with different sized applanating areas have
supported the accuracy of his formulations (202). On the basis of this formula and additional
experiments, Friedenwald developed a set of conversion tables, referred to as the 1948 and 1955 tables
for IOP. Subsequent studies indicated that the 1948 tables agree more closely with measurements by
Goldmann applanation tonometry (203, 204).
The basic technique involves positioning the patient in a supine position with a fixation target just
overhead. The examiner separates the eyelids and gently rests the tonometer footplate on the
anesthetized cornea in a position that allows free vertical movement of the plunger. When the tonometer
is properly positioned, the examiner observes a fine movement of the indicator needle on the scale in
response to the ocular pulsations. The scale reading should be taken as the average between the extremes
of these excursions. It is customary to start with the fixed 5.5-g weight. However, if the scale reading is
4 or less, additional weight should be added to the plunger. A conversion table is then used to derive the
IOP in mm Hg from the scale reading and plunger weight. Grant combined the concept of Schiötz
tonometry with continuous electronic monitoring of the pressure for use in tonography (discussed in
Chapter 3).
It is important to be aware of the potential sources of error with indentation tonometry. The accuracy
depends on the assumption that all eyes respond the same way to the external
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force of indentation, which is not the case. Because conversion tables were based on an “average”
coefficient of ocular rigidity (K), eyes that deviate significantly from this K value give false IOP
measurements. The technique for determining K is based on the concept of differential tonometry, using
two indentation tonometric readings with different weights, and the Friedenwald nomogram, as
previously discussed. Another variable that affects accuracy is expulsion of intraocular blood during
indentation tonometry (205). In addition, a relatively steep or thick cornea causes an increased
displacement of fluid during indentation tonometry, which leads to a falsely high IOP reading (206).
Miscellaneous Tonometers
Rebound Tonometer
A new handheld tonometer, the Icare tonometer (Icare Finland, Helsinki) is able to measure IOP without
the use of topical anesthetic (Fig. 2.12). IOP is determined by measuring the force produced by a small
plastic probe as it rebounds from the cornea. This device has been assessed for use in children and
adults. The rebound tonometer has been shown to have similar accuracy to the Tono-Pen, and it is
comparable with Goldmann tonometry for IOPs over a reasonable range in adults. Icare was reported to
be comfortable and highly reproducible for tonometry in healthy school-aged children (207). The Icare
tonometer has already proven valuable as a screening tool in children (see Chapter 13). The ability to
evaluate IOP without the use of topical anesthesia potentially provides the opportunity to monitor IOP at
home.
IOP Monitoring Devices
In the diagnosis and management of glaucoma, there is need for an IOP telemetry device without
artificially altering the pressure (208, 209). Several prototypes—based on a contact lens, an implantable
device, or a scleral band device (210, 211)—have been developed. Such a lens will help us monitor and
manage individuals who are susceptible to wide IOP fluctuations, who have poor adherence to medical
therapy, who perhaps are “poor responders” to medical therapy, and who have wide IOP fluctuations in
the postoperative period (212).
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Figure 2.12 Measurement of IOP using the handheld Icare rebound tonometer.
Comparison of Tonometers
The most precise method for evaluating the accuracy of a tonometer is to compare it with manometric
measurements of the cannulated anterior chamber. Although this technique is frequently used with
animal and autopsy eyes, its use in largescale human studies has been limited. The alternative is to
compare the tonometer in question against the instrument that previous studies have shown to be the
most accurate. In eyes with regular corneas, the Goldmann applanation tonometer is generally accepted
as the standard against which other tonometers must be compared. Even with this instrument, however,
inherent variability must be taken into account. When two readings were taken on the same eye with
Goldmann tonometers in a short time frame, at least 30% of the paired readings differed by 2 and 3 mm
Hg or more (213). In another study, intraobserver variation was 1.5 ± 1.96 mm Hg and interobserver
variation was 1.79 ± 2.41 mm Hg, which could be reduced by 9% and 11%, respectively, by using the
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median value of three consecutive measurements (214).
Clinically, the most widely used methods for measuring IOP are by Goldmann applanation tonometry
and with use of the Tono-Pen; the noncontact tonometer, Perkins tonometer, pneumotonometry, and the
Schiötz tonometer are not used as much. In general, the Schiötz tonometer reads lower than the
Goldmann, even when the postural influence on IOP is eliminated by performing both measurements in
the supine position (215). The Perkins applanation tonometer compared favorably against the Goldmann
tonometer (216). In a comparison of readings obtained by the Perkins tonometer, the Tono-Pen, and the
Schiötz tonometer, the greatest agreement was between the Perkins and Tono-Pen tonometers in
children under anesthesia (217).
The Tono-Pen has been compared favorably with manometric readings in human autopsy eyes (218,
219). In clinical comparisons with Goldmann applanation readings, some studies found a good
correlation, especially within the normal IOP range, although most studies agree that the Tono-Pen
underestimates Goldmann IOP in the higher range and overestimates in the lower range (195, 220).
In multiple comparative studies, readings taken with the pneumotonometer correlated closely with those
obtained by using Goldmann tonometers, although the pneumotonometer readings tended to be higher
(221, 222). In comparing IOPs in eyes before and after LASIK for myopia, pneumotonometry showed
less IOP lowering compared with Goldmann applanation tonometry after LASIK-induced cornea
thinning, which was interpreted to mean that post-LASIK IOP measurements obtained by
pneumotonometry were more reliable than those taken by Goldmann applanation (223). In cat eyes,
pneumotonometry was more accurate than the Tono-Pen, compared to the set IOPs established by
manometry (224).
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Tonometry for Special Clinical Circumstances
Tonometry on Irregular Corneas
The accuracy of Goldmann and Tono-Pen tonometers and the noncontact tonometers is limited in eyes
with irregular corneas. The pneumatic tonometer has been shown to be useful in eyes with diseased or
irregular corneas (225). In eyes after penetrating keratoplasty, the Tono-Pen significantly overestimated
Goldmann readings (226).
Tonometry over Soft Contact Lenses
It has been claimed that pneumotonometry and the Tono-Pen can measure with reasonable accuracy the
IOP through bandage contact lenses (227, 228). In cadaver eyes with four different brands of therapeutic
contact lenses, readings from the pneumotonometer correlated well with manometrically determined
IOP, whereas the Tono-Pen consistently underestimated the pressure (229).
Tonometry with Gas-Filled Eyes
Intraocular gas significantly affects scleral rigidity, rendering indentation tonometry particularly
unsatisfactory. A pneumatic tonometer underestimated Goldmann IOP measurements in eyes with
intravitreal gas, whereas measurement with the Tono-Pen compared favorably with Goldmann readings
in eyes after pars plana vitrectomy and gas-fluid exchange (230). In a study of 50 eyes with irregular
corneas after vitrectomy and air-gas-fluid exchange, readings with the Tono-Pen and pneumotonometer
were highly correlated, although there was a mean difference of 1.4 mm Hg, with the Tono-Pen usually
reading lower (220). A manometric study with human autopsy eyes indicated that both instruments
significantly underestimated the IOP at pressures greater than 30 mm Hg (231).
Tonometry with Flat Anterior Chamber
In human autopsy eyes with flat anterior chambers, IOP readings from the Goldmann applanation
tonometer, pneumotonometer, and Tono-Pen did not correlate well with manometrically determined
pressures (232).
Tonometry in Eyes with Keratoprostheses
In patients at high risk for corneal transplant rejection, implantation of a keratoprosthesis is now a viable
option for vision rehabilitation (233). However, given that most keratoprostheses have a rigid, clear
surface, it is impossible to measure IOP by using applanation or indentation instruments. In such eyes,
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tactile assessment appears to be the most widely used method to estimate IOP (234).
KEY POINTS
The mean IOP value in the general population is approximately 15 mm Hg, and two SDs to either
side of the mean gives a “normal” range of roughly 10 to 20 mm Hg.
IOP is a quantitative trait with a Gaussian distribution. IOP is an important consideration for
diagnosis of glaucoma, for setting a target pressure (discussed further in Chapter 27), and for
evaluating treatment outcomes.
IOP is influenced by genetics, environment, and physiology.
IOP is measured by essentially two different types of instruments that use either applanation
methods, such as Goldmann tonometer, or indentation, like the Schiötz tonometer.
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3 - Gonioscopy and Other Techniques for Assessing the Anterior Segment
> Table of Contents > SECTION I - The Basic Aspects of Glaucoma > 3 - Gonioscopy and Other
Techniques for Assessing the Anterior Segment
3
Gonioscopy and Other Techniques for Assessing the Anterior Segment
Assessment of the anatomy of the anterior chamber angle by gonioscopy is an essential part of the
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glaucoma evaluation. The drainage angle, as well as other structures in the anterior segment (namely,
iris insertion and ciliary body anatomy), can also be assessed by using ultrasonographic and laser
imaging techniques, and cycloscopy. In this chapter, we describe these techniques, and those involved in
the assessment of aqueous humor dynamics. Although the methods in the latter category—specifically,
tonography, fluorophotometry, and measurement of episcleral venous pressure—are not routinely used
in clinical practice today, clinicians should be familiar with them because their results form our
understanding of aqueous humor dynamics and the mechanism of action of glaucoma medications used
to lower intraocular pressure (IOP).
GONIOSCOPY
This discussion of gonioscopy is limited to technique and normal anatomic findings, whereas abnormal
findings on gonioscopic examination associated with the various forms of glaucoma are considered in
Section II.
Historical Background
In 1907, Trantas visualized the angle in an eye with keratoglobus by indenting the limbus. He later
coined the term gonioscopy. Salsmann introduced the goniolens in 1914, and Koeppe improved on it 5
years later by designing a steeper lens. Troncoso also contributed to gonioscopy by developing the
gonioscope for magnification and illumination of the angle. In 1938, Goldmann introduced the
gonioprism, and Barkan established the use of gonioscopy in the management of glaucoma. (More
details on the history of gonioscopy are available in a review by Dellaporta (1).)
Principle of Gonioscopy
In healthy eyes, the angle cannot be visualized directly because of the optical principle known as the
critical angle. The critical angle is related to the properties of light passing through media with different
indices of refraction. When light passes from a medium with a greater index of refraction to one with a
lesser index, the angle of refraction (r) is larger than the angle of incidence (i). When r equals 90
degrees, i is said to have attained the critical angle. When i exceeds the critical angle, the light is
reflected back into the first medium. The critical angle for the cornea-air interface is approximately 46
degrees. Light rays coming from the anterior chamber angle exceed this critical angle and are therefore
reflected back into the anterior chamber, preventing direct visualization of the angle (Fig. 3.1A-D).
The solution to this problem is to eliminate the cornea-air interface by using a goniolens or gonioprism.
Because the index of refraction of a contact lens approaches that of the cornea, there is minimal
refraction at the interface of these two media, which eliminates the optical effect of the front corneal
surface. Therefore, light rays from the anterior chamber angle enter the contact lens and are then made
to pass through the new contact lens-air interface by one of two basic designs. In direct gonioscopy, the
anterior curve of the contact lens—the goniolens—is such that the critical angle is not reached, and the
light rays are refracted at the contact lens-air interface. In indirect gonioscopy, the light rays are
reflected by a mirror in the contact lens—the gonioprism— and leave the lens at nearly a right angle to
the contact lens-air interface (Fig. 3.1 E,F). (Commonly used goniolenses and gonioprisms are listed in
Table 3.1, and some are shown in Fig. 3.2.)
Direct Gonioscopy
Instruments
The Koeppe lens is the prototype diagnostic goniolens and is available in different diameters and radii of
posterior curvature. A gonioscope, or handheld biomicroscope, provides 15 × to 20 × magnification. The
light source is usually a separate handheld unit, such as the Barkan focal illuminator, although it may be
attached to the gonioscope.
Technique
Direct gonioscopy is performed with the patient in a supine position, preferably on a movable diagnostic
table or chair. After applying a topical anesthetic, the goniolens is positioned on the cornea, with either
balanced salt solution, a viscous preparation such as methylcellulose, or the patient's own tears between
the goniolens and the patient's cornea. The examiner usually holds the gonioscope in one hand and a
light source in the other (Fig. 3.3). Occasionally, an assistant may be needed to move the goniolens to
the desired position. Alternatively, a gonioscope with mounted light source may be used, which allows
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the examiner to control the goniolens with the other hand. In either case, the examiner scans the anterior
chamber angle by shifting his or her position until all 360 degrees have been studied. An excellent
overview of direct gonioscopy, with guided video gonioscopy examinations, is available at
http://www.gonioscopy.org/.
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Figure 3.1 Principle of gonioscopy. A: Light ray is refracted when angle of incidence (i) at interface of
two media with different indices of refraction (n and n) is less than the critical angle. B: Angle of
refraction (r) is 90 degrees when i equals the critical angle. C: Light is reflected when i exceeds the
critical angle. D: Light from the anterior chamber angle exceeds the critical angle at the cornea-air
interface and is reflected back into the eye. E and F: Contact lenses have an index of retraction (n)
similar to that of the cornea, allowing light to enter the lens and then be refracted (goniolens) or
reflected (gonioprism) beyond the contact lens-air interface.
Table 3.1 Contact Lenses for Gonioscopy
LensDescription/Use
Goniolenses (direct gonioscopy)
Koeppe
Prototype diagnostic goniolens
Richardson-Shaffer
Small Koeppe lens for use in infants
Layden
For gonioscopic examination of premature infants
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Barkan
Prototype surgical goniolens
Thorpe
Surgical and diagnostic lens for operating rooms
Swan-Jacob
Surgical goniolens for use in children
Gonioprisms (indirect gonioscopy)
Goldmann singleMirror inclined at 62 degrees for gonioscopy
mirror
Goldmann three-mirror One mirror for gonioscopy, two for retina; coated front surface available for
laser use
Zeiss four-mirror
All four mirrors inclined at 64 degrees for gonioscopy; requires holder
(Unger); fluid bridge not required
Posner four-mirror
Modified Zeiss four-mirror gonioprism with attached handle
Sussman four-mirror Handheld Zeiss-type gonioprism
Thorpe four-mirror
Four gonioscopy mirrors, inclined at 62 degrees requires fluid bridge
Ritch trabeculoplasty Four gonioscopy mirrors, two inclined at 59 degrees and two at 62 degrees,
lens
with convex lens over two
Latina trabeculoplasty One mirror for trabeculoplasty
lens
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Figure 3.2 Representative indirect and direct goniolenses. Top row, from left to right: large Goldmann
three-mirror indirect goniolens, small Goldmann three-mirror indirect goniolens, and Latina indirect
goniolens. Middle row: Zeiss four-mirror indirect goniolens with Unger holder. Bottom row, from left:
adult Koeppe direct goniolens, Leyden direct goniolens, and four-mirror Sussman indirect goniolens.
Indirect Gonioscopy
Instruments
The gonioprism and a slitlamp are the only instruments needed for indirect gonioscopy. Several types of
goniolenses are available with a single mirror or multiple mirrors. The Goldmann single-mirror lens is
tilted 62 degrees from the plano front surface, which allows examination of the anterior chamber angle.
The Goldmann three-mirror lens contains two mirrors for examination of the fundus, and one for
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examination of the angle. Because of their 7.38-mm posterior radius of curvature, both Goldmann lenses
require the use of a viscous material to fill the space between the cornea and the lens. In contrast, a
modified Goldmann-type lens, with its 8.4-mm radius of curvature, requires no viscous bridge (2).
Goldmann-type lenses have also been modified with antireflection coating, allowing them to be used for
laser trabeculoplasty.
Figure 3.3 Technique of direct gonioscopy, by using a Koeppe goniolens and portable slitlamp, during
an examination under anesthesia of a child's eye.
In the Zeiss four-mirror lens, all the mirrors are tilted at 64 degrees for evaluation of the angle,
eliminating the need to rotate the lens. The original four-mirror lens is mounted on a holding fork (an
Unger holder), whereas newer models have a permanently attached holding rod (a Posner lens) or are
held directly, such as the Sussman-style lenses (3). The posterior curvature of these four-mirror lenses is
similar to that of the cornea, conveniently allowing the patient's own tears to be used as the fluid bridge.
With the Goldmann- and Zeiss-type instruments, the anterior chamber angle is viewed “indirectly”
through a mirror 180 degrees from the quadrant being viewed (Fig. 3.4). Some newer gonioprisms
enable direct viewing of the angle (4, 5).
Several types of lenses, including the Ritch trabeculoplasty lens and the Latina lens, are used in laser
therapy (discussed in Section III).
Technique
The cornea is anesthetized and, with the patient positioned at the slitlamp, the gonioprism is placed
against the cornea with or without a fluid bridge, depending on the posterior radius of
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curvature of the instrument. The lens is then rotated to allow visualization of all 360 degrees of the
angle, or the quadrants are studied with the four mirrors. Visualization into a narrow angle can be
enhanced by manipulating the gonioprism—for example, asking the patient to look in the direction of
the mirror being used. A web-based gonioscopy module with video, available at www.gonioscopy.org,
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is recommended for learning this technique (4).
Figure 3.4 Technique of indirect gonioscopy with a Zeiss four-mirror lens (A) and a Goldmann threemirror lens (B).
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Comparison of Direct and Indirect Gonioscopy
There is no unanimity of opinion on which basic method of gonioscopy is best. With direct gonioscopy,
the height of the observer may be changed to look deeper into a narrow angle, whereas the gonioprism is
limited in this regard by the height of the mirror. In addition, the goniolens may cause less distortion of
the anterior chamber. Both features make it desirable when assessing the true depth of the anterior
chamber angle (5). A major advantage of direct gonioscopy, especially with the infant Koeppe lenses, is
its use in sedated or anesthetized patients, as in the examination of children. These lenses are also useful
in examining the fundus through a small pupil with a direct ophthalmoscope.
In indirect gonioscopy, the slitlamp may provide better optics and lighting, which could be an advantage
when looking for subtle details in the angle. Furthermore, the method requires fewer additional
instruments and occupies less space than direct gonioscopy does. Indirect gonioscopy is also performed
faster than direct gonioscopy is; this is particularly true with the Zeiss four-mirror lenses and modified
Goldmann-type lenses, because no viscous bridge is required. Gonioprisms with a posterior radius of
curvature closer to that of the anterior corneal surface may also reduce corneal distortion. Gonioprisms
with taller mirrors facilitate visualization of narrow angles. Finally, because of its relatively small
diameter of corneal contact, the Zeiss four-mirror lens can also be used in “compressive gonioscopy” (6)
(explained in Chapter 12).
Figure 3.5 Normal adult anterior chamber angle showing gonioscopic appearance (right) and cross
section of corresponding structures (left). 1. Ciliary body band; 2. scleral spur; 3. trabecular meshwork
(degree of pigmentation varies); 4. Schwalbe line.
Cleaning of Diagnostic Contact Lenses
Any instrument that contacts the eye creates the potential hazard of transmitting bacterial and viral
infection. This issue is considered in more detail in Chapter 2. (Although Chapter 2 discusses instrument
cleaning in the context of tonometry use, the same basic principles apply with diagnostic contact lenses
(7).)
Gonioscopic Appearance of the Normal Anterior Chamber Angle
Starting at the root of the iris and progressing anteriorly toward the cornea, the following structures can
be identified by gonioscopy in an adult with a normal angle (Figs. 3.5 and 3.6).
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Ciliary Body Band
The ciliary body band is the portion of ciliary body visible in the anterior chamber as a result of the iris
insertion into the ciliary body. The width of the band depends on the level of iris insertion, and tends to
be wider in myopic eyes and narrower in hyperopic eyes. The color of the band is usually gray or dark
brown.
Scleral Spur
This is the posterior lip of the scleral sulcus, which is attached to the ciliary body posteriorly and the
corneoscleral meshwork anteriorly. It is usually seen as a prominent white line between the ciliary body
band and functional trabecular meshwork,
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unless it is obscured by dense uveal meshwork or excessive pigment dispersion. Variable numbers of
fine, pigmented strands may frequently be seen crossing the scleral spur from the iris root to the
functional meshwork. These are referred to as iris processes, and represent thickenings of the posterior
uveal meshwork.
Figure 3.6 A: Going from the iris (l) to the cornea (C), the structures normally seen by gonioscopy in the
open, adult anterio chamber angle are the ciliary body band (CBB), scleral spur (SS), and the functional
portion of the trabecular meshwork (TM). B: In this eye, the ciliary body band is light gray; trabecular
meshwork is heavily pigmented. The thinner, pigmented line above the meshwork (arrow) is the
Schwalbe line, more easily seen in some eyes because of pigment buildup along the ridge, especially in
the inferior quadrant. C: Whereas the ciliary body band may appear dark brown in some eyes (e.g., A,
above), it may be a slate gray band in others, as seen in this image just above the iris root. Also note the
numerous iris processes, which typically extend across the ciliary body band and scleral spur to the
trabecular meshwork, which is medium brown in this image. D: Sometimes helpful in identifying the
location of a lightly pigmented trabecular meshwork is blood reflux in the Schlemm canal (arrow).
Functional Trabecular Meshwork
This is seen as a pigmented band just anterior to the scleral spur. Although the trabecular meshwork
actually extends from the iris root to Schwalbe line, it may be considered in two portions: (a) the
anterior part, between the Schwalbe line and the anterior edge of the Schlemm canal, which is involved
to a lesser degree in aqueous outflow, and (b) the posterior (or functional) part, which is the remainder
of the meshwork and is the primary site of aqueous outflow (especially that portion immediately
adjacent to the Schlemm canal) (8).
The appearance of the functional meshwork varies considerably depending on the amount and
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distribution of pigment deposition. The trabecular meshwork has no pigment at birth, but with age, color
develops, from faint tan to dark brown, depending on the degree of pigment dispersion in the anterior
chamber. The distribution of pigment may be homogeneous for 360 degrees in some eyes and irregular
in others. In the functional portion of the meshwork, especially when lightly pigmented, blood reflux in
the Schlemm canal may sometimes be seen as a red band.
Schwalbe Line
The Schwalbe line is the junction between the anterior chamber angle structures and the cornea. It is a
fine ridge just anterior to the meshwork and is often identified by a small buildup of pigment, especially
inferiorly. By using a thin slit beam at a slightly oblique angle, this line can be identified by the corneal
wedge created by light wedge created at the junction between the inner light beam along the cornea
endothelium and the outer light beam along the corneoscleral junction.
Normal Blood Vessels
Blood vessels are normally not seen in the angle, although loops from the major arterial circle may
appear in front of the ciliary body band and less commonly over the scleral spur and trabecular
meshwork. These vessels typically take a circumferential route in the angle.
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In addition, an anterior ciliary artery may occasionally be seen as a more radially oriented vessel in the
ciliary body band of lightly pigmented eyes. Circumferential and radial vessels may also occasionally be
seen in the peripheral iris of lightly colored eyes. In a study of 100 patients with abnormal anterior
chamber angle vascularization of unknown cause, 16 patients had normal angle vessels in both eyes and
10 patients had normal angle vessels in one eye (9). Radial vessels were more common in the peripheral
iris, whereas the circumferential type was more common on the ciliary body band.
Recording Gonioscopic Findings
Various classification systems have been suggested for describing the width and appearance of the
anterior chamber angle. However, descriptive words and drawings are probably the most useful
technique for recording gonioscopic findings. The recorded data should include (a) configuration of the
angle, (b) depth of the angle on the basis of the most posterior structure that can be seen, (c) degree of
pigmentation, and (d) presence of abnormal structures. For example, a normal angle might be recorded
as “wide open, with visualization to a wide ciliary body band for 360 degrees and moderate trabecular
meshwork pigmentation.” Drawings can also be placed on a chart with concentric circles to document
more specific details.
CYCLOSCOPY
This technique allows direct visualization of ciliary processes under special circumstances, such as the
presence of an iridectomy, wide iris retraction, aniridia, and some patients with aphakia. The main value
of the technique is in conjunction with laser therapy to the ciliary processes (transpupillary
cyclophotocoagulation, discussed in Section III).
HIGH-RESOLUTION ULTRASOUND BIOMICROSCOPY
Another useful clinical tool to examine the anterior ocular segment is ultrasound technology. Ultrasound
echoes are produced from interfaces of fluids and tissues. The differences between fluid or tissue
properties yield certain echo characteristics between the interfaces of various compartments or tissue
densities. The echo is optimal when the acoustic wave is oriented perpendicular to the interface.
Ultrasonographic techniques can provide information in the amplitude mode, or A-scan, or in the
brightness mode, or B-scan.
In general, low-frequency ultrasonography allows deeper tissue penetration but lower resolution,
compared with highfrequency ultrasonography, which provides higher resolution but shallower
penetration. There is a wide range of frequencies currently in use in ophthalmology, from 10 MHz, to
image the globe and orbit, through 20 MHz, which images from the cornea to the posterior lens, 35 to 50
MHz, which image from the cornea to the anterior lens, and 100 MHz, for imaging the cornea only (Fig.
3.7). Frequencies of 20 to 50 MHz, which are used to image the anterior segment, are referred to as
highresolution ultrasound biomicroscopy (10).
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Figure 3.7 Schematic representation of penetration of acoustic sound waves by different ultrasound
frequencies. (Modified with permission from Cynthia Kendall.)
High-resolution ultrasound biomicroscopy allows for a noninvasive means of visualizing anterior ocular
structures at high resolution. In the management of patients with glaucoma, high-resolution ultrasound
biomicroscopy is helpful to define the anterior chamber angle anatomy, when it cannot be seen
gonioscopically, as well as structure and relationships among the iris, ciliary body, crystalline lens,
intraocular lens, and anterior vitreous. (The use of high-resolution ultrasound biomicroscopy in
managing the various forms of glaucoma is considered in Section II.)
OPTICAL COHERENCE TOMOGRAPHY OF THE ANTERIOR SEGMENT
Introduced in 2006, anterior-segment optical coherence topography, or AS-OCT, provides a noncontact,
noninvasive means to image the anterior chamber angle anatomy (11, 12). The AS-OCT uses a 1310-nm
wavelength, compared with the 820-nm wavelength for posterior-segment imaging. The AS-OCT has
higher resolution, compared with high-resolution ultrasound biomicroscopy, for imaging structures in
the iris and the angle anatomy. The AS-OCT is limited to imaging the cornea, anterior chamber, angle
anatomy, and central portion of the lens through the pupil (Fig. 3.8). This instrument is unable to
adequately image the anatomy of the ciliary body or tissue masses behind the iris.
AQUEOUS HUMOR DYNAMICS
There are several techniques used to measure and calculate the determinants of IOP, which include
aqueous humor flow, facility of aqueous outflow, uveoscleral outflow, and episcleral
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venous pressure (13). These techniques include (a) fluorophotometry, a noninvasive and noncontact
technique to measure the rate of fluorescein disappearance from the anterior segment and to calculate
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aqueous humor flow; (b) tonography, a noninvasive but contact technique to estimate the facility of
aqueous outflow; and (c) the episcleral venometer, a noninvasive but contact technique to estimate
episcleral venous pressure.
Figure 3.8 Montage of anterior-segment OCT images showing normal anterior segment (A), iris cyst
(B), and subluxated lens with shallow anterior chamber and narrow angle (C).
Mathematical Models for IOP
The mathematical relationship of the determinants of IOP is based on Poiseuille law that relates the
velocity of flow (F) of fluid in a rigid tube to the following: the radius of the tube (r), the pressure drop
per length of tube [(P1 — P2)/1], and the coefficient of viscosity (?) of the fluid
(http://hyperphysics.phy-astr.gsu.eu/hbase/ppois.html):
In 1949, Goldmann applied Poiseuille law to aqueous outflow (14). Goldmann proposed that the rate of
aqueous flow through the trabecular meshwork (F) is directly proportional to the IOP (P0) minus the
episcleral venous pressure (Pv) and inversely proportional to the resistance to outflow (R):
Building on earlier observations by Pagenstecher (in 1878) and Schiotz (in 1905) that eye massage and
repeated tonometry reduced IOP, Polak-van Gelder in 1911 described a technique of repeated tonometer
applications for 1 to 2 minutes to differentiate healthy from glaucomatous eyes. Schoenberg modified
this technique by using a continuous application of the tonometer while reading the pressure fall on the
scale of the instrument. Later in 1950, Grant introduced tonography using electronic continuous IOP
measurement and proposed an alternative factor to collectively express “outflow resistance” as the
coefficient of outflow facility (C), which is reported in microliters per minute per millimeter of mercury
in the following equation (15):
F= C(P0 — Pv) The C value is an expression of the degree to which a change in the IOP will cause a
change in the rate of aqueous outflow, which is an indirect expression of the patency of the aqueous
outflow system.
The Goldmann equation implied that aqueous flow in living ocular tissue could be expressed in the same
linear terms as that of fluid in rigid tubes, which was subsequently proven inaccurate. Nevertheless, it
has served for over 50 years as an adequate description of aqueous humor dynamics for clinical
applications. Recent advances in glaucoma therapeutics, namely the prostaglandin agents (described in
Chapter 28), have made it necessary to revise the equation and to reinterpret the meanings of its
parameters to the following equation (13) presented in a form based on IOP, using the variables of
aqueous flow (Fa), uveoscleral flow (Fu), trabecular outflow facility (Ct), and episcleral venous pressure
(EVP):
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Fluorophotometry
Fluorophotometry is the standard research technique by which the rate of aqueous humor flow is
calculated under various circumstances, including the response to glaucoma drugs.
In brief, the fluorophotometry protocol involves instilling a given number of drops of saturated
fluorescein topically, waiting for an appropriate period of time for steady state distribution of the
fluorescein in the anterior segment structures of the cornea and anterior chamber, and then scanning the
eye two or three times to obtain appropriate emission scans (16). Calculations are made on the basis of
the change in fluorescein measured in the cornea and anterior chamber over time.
In a study of 519 subjects, there is a skewed normal distribution of aqueous humor flow measured
between 8 AM and noon with an average of 2.97 (µL/min (16). Among 180 normal subjects studied
between midnight and 6 AM, there was decrease in aqueous humor flow to half of the morning flow
value and with a narrower distribution of flow. A later study showed concordance of flow in normal
subjects in the morning and night (17) meaning that individuals who had either low, medium, or high
aqueous flow phenotypes in the morning showed the expected decrease in flow at night time, but also
had a relatively low, medium, or high flow at night, respectively. This latter approach to characterize
aqueous flow as a phenotype provides evidence that the factors that contribute to IOP can be studied as a
quantitative trait (18). At present, there are no genetic markers for IOP variance, but genome-wide
studies currently under way hold the promise of identifying such markers that may be important in
identifying patients who have wide IOP fluctuation. In the future, such a molecular medicine approach
(see Chapter 8) will help minimize glaucoma progression in patients with wide IOP fluctuation.
In general, aqueous humor flow decreases with age (16, 19). Fluorophotometric studies suggest that
aqueous production is relatively insensitive to long-term changes in IOP (20). It
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appears that the main mechanism involved in elevated IOP is alteration in outflow facility (21), which is
related to increased resistance to outflow at the trabecular meshwork to a greater extent than the
uveoscleral outflow, rather than a “hyper secreter,” but the role of high aqueous flow phenotype in large
IOP fluctuation is not known. Resistance to aqueous outflow increases with an increase in the IOP (the
physiologic basis of which is discussed in Chapter 1). The tonographic result is that the C value of an
eye decreases with increasing IOP (21), which is related to trabecular outflow, also described as
conventional outflow, which is discussed in the next section on tonography.
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Figure 3.9 Tonography unit.
At present, there is no method to measure uveoscleral outflow, also described as unconventional
outflow. The influence of unconventional outflow on the tonographic results (discussed in the next
section) is not fully understood. At present, the uveoscleral outflow is calculated on the basis of
measurements derived from fluorophotometry and tonography (22, 23).
Tonography
Tonography is a means of estimating the outflow facility by raising the IOP with an electronic
indentation tonometer and observing the subsequent decay curve in the IOP over time, which is
continuously recorded on a paper strip (Figs. 3.9 and 3.10). The elevated pressure causes an increased
rate of aqueous outflow, leading to a change in the aqueous volume (V), which is inferred from
Friedenwald tables (24).
In brief, the protocol involves measurements on a patient in a supine position. After measuring the IOP,
a weighted tonometer raises the IOP from the baseline (P0) to a new, higher level (Pt). Depending on the
instrument, a 2- or 4-minute pressure tracing is recorded by gently applying the tonometer to the cornea
and maintaining this position until a smooth tracing has been obtained. A good tracing will have fine
oscillations and a gentle downward slope. If the slope is steeper or irregular during the first few seconds,
which is not uncommon, the study is continued until a smooth tracing is obtained.
The slope of the tracing is estimated by placing a line through the middle of the oscillations. The change
in IOP during this time is computed as an arithmetic average of pressure increments for successive halfminute intervals [Ave.(Pt — P0)]- The scale readings are noted at the beginning and end of the tracing.
P0 and the change in scale readings over 4 minutes (T) are then used to obtain the C value from special
tonographic tables derived from Grant's equation:
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Figure 3.10 Tonographic tracing.
The wave components of a tonographic tracing include (a) fine oscillations, which reflect the cardiac
pulse; (b) large waves, which reflect the respiratory movement; and (c) still larger, irregular waves
(Traube-Hering waves), which reflect periodic oscillations in the systemic blood pressure. Cardiac
irregularities (e.g., extrasystole, bigeminy) can also cause irregularities in the tonographic tracing (25).
Aqueous production may decrease during the early phase of a rise in IOP, primarily because of an
alteration in ultrafiltration (26). Any subsequent IOP drop in response to reduced production of aqueous
creates an impression of increased outflow and is called pseudofacility. This may account for as much as
20% of the total C value. Tonography measures the total C value without distinguishing between true
facility and pseudofacility.
In a study of 1379 eyes, Becker reported a mean C value of 0.28 µL/min/mm Hg in 909 healthy eyes
(27). A low C value of less than 0.18 µL/min/mm Hg was found in 2.5% of healthy eyes, 65% of those
with glaucoma (N= 250 eyes), and 20% of those with a family history of glaucoma (N= 220 eyes). An
even lower C value, of less than 0.13 µL/min/mm Hg, was recorded for 0.15%, 3%, and 11%,
respectively. The P0/C ratio was 56 in the healthy populations. The proportion of participants with a
high P0/C ratio of greater than 100 was 2.5% among healthy eyes, 95% among those with glaucoma, and
31% in those with a family history of glaucoma. An even higher P0/C ratio, of greater than 138, was
found among 0.15% of healthy eyes, 50% of those with glaucoma and 14% of those with a family
history of glaucoma.
In a study of 7577 eyes, the C value was found to decrease with age, with an average of 0.29
µL/min/mm Hg for those aged 41 to 45 years, compared with 0.25 µL/min/mm Hg in those aged 81 to
85 years (28). No differences by sex were found for any age-group.
The tonographic method has several sources of error. First, this technique was developed with several
major assumptions.
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The calculations assume that only the rate of aqueous outflow changes in response to a change in IOP.
However, many other ocular parameters, such as ocular blood volume (29) and ocular rigidity, also
respond to pressure change, and all of them can affect the tonographic result. Ocular rigidity is an
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expression of the “stretchability” of the eye and represents elasticity and viscoelastic properties of the
eye (30, 31 and 32). An average ocular rigidity coefficient of 0.013 mmHg/µL was used for calculating
the tonographic C value, which leads to a potential source of error because of significant interpatient
variation in this parameter. For this reason, it is useful to check the pressure by applanation tonometry
before performing the tonography and to compare this with the P0 obtained with the indentation
tonometer, to identify any major discrepancy in ocular rigidity. Another assumption was that the C value
calculations from each minute did not differ significantly; however, this was shown to be invalid, with a
trend toward highest values in the first minute and progressive reduction in the ensuing minutes (33).
Last, the corneal curvature was assumed as an average of 7.8 mm, but variations in the cornea may
significantly influence the pressure measurements.
Second, there were some instrumentation and operating issues that contributed as a source of error. The
instrument was designed with a larger hole in the electronic tonometer footplate to prevent sticking. At
low scale readings, the cornea may mold into the space between the plunger and hole, pushing the
plunger up and leading to falsely high pressure readings (34). During the time of these studies, variations
in line voltage could produce a drift in the IOP measurements, which was minimized with line voltage
stabilizers and by avoiding magnetic fields.
Third, several patient factors influence tonography studies. The IOP has been shown to drop
approximately 1 mm Hg in the fellow eye while tonography is being performed on the first eye. This
consensual pressure drop was once thought to have a neural cause, but it was subsequently found to be
secondary to the evaporation that results from keeping the eye open for fixation during the 4-minute test
(35). In addition, eye movement affected IOP measurements, which was described as a “patientrelaxation effect” during the first 15 to 20 seconds after the tonometer is placed on the cornea. So,
additional time was allowed for this before starting the 4-minute tracing.
Fourth, operator error, including improper cleaning leading to a sticky tonometer, calibration, or
positioning of the instrument, and improper calculation of the tracing, can also lead to inaccurate results.
Measurement of Episcleral Venous Pressure
Various techniques have been developed for measuring the pressure in the episcleral veins. All of these
work on the principle of correlating partial collapse of the vein with the force required to achieve the
alteration in blood flow (36). A pressure-chamber technique uses a thin membrane stretched over the tip
of a hollow applanating head, which is filled with air or saline. The pressure in the chamber is raised
until the bulging membrane produces the desired visible change in the adjacent vessel. Most of these
instruments are mounted on a slitlamp, although a portable pressure transducer has been developed to
measure episcleral venous pressure with a patient in various body positions (37). When comparing a
torsion balance instrument and a pressure chamber technique to direct cannulation of the episcleral vein,
the pressure chamber method was found to be superior to the torsion technique (38).
The normal episcleral venous pressure is generally considered to be between 8 and 11 mm Hg. Two
features that significantly influence the measured pressure are the selected endpoint and the choice of
vessel. When a pressure chamber technique was compared to direct cannulation, a slight indentation,
rather than an intermittent or sustained collapse of the vein lumen, gave the most accurate reading (39).
It has been suggested that the best point of measurement is just distal to the junction of aqueous and
episcleral veins, although this junction is often difficult to ascertain and it may be more practical to take
all measurements 3 mm from the limbus (36).
Episcleral venous pressure rises an average of 1.25 mm Hg with the pressure elevation during
tonography (40), which is usually corrected for in the formula by adding 1.25 to P0. Episcleral venous
pressure measurements throughout tonography indicate that the rise is greatest during the first half of
tonography, with a return to a nearly pretonographic level by the end of the procedure and a mean
change in episcleral venous pressure during this time of 0.44 mm Hg.
KEY POINTS
Gonioscopy is an essential tool used to evaluate patients with glaucoma to assess the angle
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anatomy.
High-resolution ultrasound biomicroscopy and anteriorsegment OCT are imaging methods to
evaluate the drainage angle. High-resolution ultrasound biomicroscopy can evaluate structures,
such as the ciliary body and suspicious masses, behind the iris.
Aqueous humor flow, trabecular outflow, uveoscleral outflow, and episcleral venous pressure are
the four physiological components of IOP. Functional assessment of these dynamic components is
possible using fluorophotometry tonography, and venomanometry
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2. Kapetansky FM. A bubble-free goniolens. Ophthalmic Surg. 1988;19(6): 414-416.
3. Sussman W. Ophthalmoscopic gonioscopy. Am J Ophthalmol. 1968; 66(3):549.
4. Alward WLM. Available at: http://www.gonioscopy.org/. Iowa City; 2009.
5. Campbell DG. A comparison of diagnostic techniques in angle-closure glaucoma. Am J Ophthalmol.
1979;88(2):197-204.
6. Forbes M. Gonioscopy with corneal indentation. A method for distinguishing between appositional
closure and synechial closure. Arch Ophthalmol. 1966;76(4):488-492.
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1984;28(4):339-348.
9. Shihab ZM, Lee PF. The significance of normal angle vessels. Ophthalmic Surg. 1985;16(6):382-385.
10. Pavlin CJ, Foster FS. Ultrasound biomicroscopy. High-frequency ultrasound imaging of the eye at
microscopic resolution. Radiol Clin North Am. 1998;36(6):1047-1058.
11. Radhakrishnan S, Huang D, Smith SD. Optical coherence tomography imaging of the anterior
chamber angle. Ophthalmol Clin North Am. 2005;18(3):375-381.
12. Ahmed IK, Lee RH. Utilization of Visante OCT for glaucoma evaluations. In: Steinert RF, Huang D,
eds. Anterior Segment Optical Coherence Tomography. Thorofare, NJ: SLACK Inc.; 2008:89-106.
13. Brubaker RF. Goldmann's equation and clinical measures of aqueous dynamics. Exp Eye Res.
2004;78(3):633-637.
14. Goldmann H. Augendruck and gluakom. Die Kammer-wasservenen und das Poiseuille'sche Gesetz.
Ophthalmologica. 1949;118:496-519.
15. Grant W. Tonographic method for measuring the facility and rate of aqueous flow in human eyes.
In: Civan MM, ed. The Eye's Aqueous Humor, From Secretion to Glaucoma. New York, NY: Academic
Press; 1998:234-284.
and at night in normal humans. Invest Ophthalmol Vis Sri. 2006;47(11):4860-4864.
18. Iyengar SK. The quest for genes causing complex traits in ocular medicine: successes,
interpretations, and challenges. Arch Ophthalmol. 2007;125(1):11-18.
19. Toris CB, Koepsell SA, Yablonski ME, et al. Aqueous humor dynamics in ocular hypertensive
patients. J Glaucoma. 2002;11(3):253-258.
20. Carlson KH, McLaren JW, Topper JE, et al. Effect of body position on intraocular pressure and
aqueous flow. Invest Ophthalmol Vis Sci. 1987; 28(8):1346-1352.
21. Moses RA. Constant pressure applanation tonography. 3. The relationship of tonometric pressure to
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rate of loss of ocular volume. Arch Ophthalmol. 1967;77(2):181-184.
22. Alm A, Nilsson SF. Uveoscleral outflow—a review. Exp Eye Res. 2009; 88(4):760-768.
Ophthalmol. 1999;127(4):407-412.
24. Hetland-Eriksen J, Odberg T. Experimental tonography on enucleated human eyes. II. The loss of
intraocular fluid caused by tonography. Invest Ophthalmol. 1975;14:944-947.
25. Haik GM, Francisco Perez L, Reitman HS, et al. Tonographic tracings in patients with cardiac
rhythm disturbances. Am J Ophthalmol. 1970; 70(6):929-934.
26. Kupfer C. Clinical significance of pseudofacility. Sanford R. Gifford Memorial Lecture. Am J
Ophthalmol. 1973;75(2):193-204.
27. Becker B. Tonography in the diagnosis of simple (open-angle) glaucoma. Trans Am Ophthalmol
Otololaryngol. 1961;65:156-162.
28. Johnson LV. Tonographic survey. Am J Ophthalmol. 1966;61:680-689.
29. Fisher RF. Value of tonometry and tonography in the diagnosis of glaucoma. Br J Ophthalmol.
1972;56(3):200-204.
30. Johnson CS, Mian SI, Moroi S, et al. Role of corneal elasticity in damping of intraocular pressure.
31. Glass DH, Roberts CJ, Litsky AS, et al. A viscoelastic biomechanical model of the cornea describing
the effect of viscosity and elasticity on hysteresis. Invest Ophthalmol Vis Sci. 2008;49(9):3919-3926.
32. Downs JC, Suh JK, Thomas KA, et al. Viscoelastic material properties of the peripapillary sclera in
normal and early-glaucoma monkey eyes. Invest Ophthalmol Vis Sci. 2005;46(2):540-546.
33. Armaly MF. Continuity of the tonography curve. II. Analysis of 1-minute intervals of the clinical
tonogram [in German]. Klin Monbl Augenheilkd. 1984;184(4):299-302.
34. Moses R. Tonometry-effect of tonometer footplate hole on scale reading; further studies. AMA Arch
Ophthalmol. 1959;61(3):373-375.
35. Grant WM, English FP. An explanation for so-called consensual pressure drop during tonography.
36. Zeimer RC, Gieser DK, Wilensky JT, et al. A practical venomanometer. Measurement of episcleral
venous pressure and assessment of the normal range. Arch Ophthalmol. 1983;101(9):1447-1449.
37. Friberg TR. Portable transducer for measurement of episcleral venous pressure. Am J Ophthalmol.
1986;102(3):396-397.
38. Brubaker RF. Determination of episcleral venous pressure in the eye. A comparison of three
methods. Arch Ophthalmol. 1967;77(1): 110-114.
39. Gaasterland DE, Pederson JE. Episcleral venous pressure: a comparison of invasive and noninvasive
measurements. Invest Ophthalmol Vis Sci. 1983;24(10):1417-1422.
40. Leith AB. Episcleral venous pressure in tonography. Br J Ophthalmol. 1963;47:271-278.
Say thanks please
4 - Optic Nerve, Retina, and Choroid
> Table of Contents > SECTION I - The Basic Aspects of Glaucoma > 4 - Optic Nerve, Retina, and
Choroid
4
Optic Nerve, Retina, and Choroid
Glaucoma is characterized by progressive atrophy of the optic nerve head secondary to the loss of optic
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nerve fiber. Because it is this pathologic alteration that leads to the irreversible loss of vision, an
understanding of glaucomatous optic atrophy is essential in the diagnosis and management of glaucoma.
ANATOMY AND HISTOLOGY
Terminology
In the context of a discussion on glaucoma, the optic nerve head is defined as the distal portion of the
optic nerve that is directly susceptible to intraocular pressure (IOP) elevation. In this sense, the optic
nerve head extends anteriorly from the retinal surface to the myelinated portion of the optic nerve that
begins just behind the sclera, posterior to the lamina cribrosa. The term optic nerve head is generally
preferred over optic disc because the latter suggests a flat structure without depth. However, the terms
disc and papilla are frequently used when referring to the portion of the optic nerve head that is
clinically visible by ophthalmoscopy (1). It is the optic nerve head and nerve fiber layer containing
retinal ganglion cell (RGC) axons that are most clearly associated with glaucomatous vision loss (Fig.
4.1).
General Description
The optic nerve head comprises the nerve fibers that originate in the ganglion cell layer of the retina and
converge upon the nerve head from all points in the fundus. At the surface of the nerve head, these RGC
axons bend acutely to exit the globe through a fenestrated scleral canal, called the lamina cribrosa. In the
nerve head, the axons are grouped into approximately 1000 fascicles, or bundles, and are supported by
astrocytes. There is considerable variation in the size of the optic nerve head. In one study, the diameter
varied from 1.18 to 1.75 mm (2). Other studies have revealed ranges of 0.85 to 2.43 mm in the shortest
diameter and 1.21 to 2.86 mm in the longest (3), or a mean of 1.88 mm vertically and 1.77 mm
horizontally (4). The disc area may range from 0.68 mm2 to 4.42 mm2 (3). In a large, population-based
study, the average disc area was 2.42 mm2 (5). In a different study, the average disc area was 2.56 mm2
when measured by the Heidelberg retina tomograph (HRT) and 2.79 mm2 by the analysis of disc
photographs (6). When optic nerve head area and neuroretinal rim area were determined in 36 radial 10degree segments on stereophotographs, cup area had stronger correlation with the disc area than the rim
area, suggesting that correction for disc size may be more important for cup area than for rim area (7).
Another study showed a positive correlation between the optic disc size and the thickness of the
peripapillary retinal nerve fiber layer (RNFL) (8).
Studies using a confocal scanning laser tomograph showed that in healthy eyes the neuroretinal rim area
and optic disc diameter have a higher correlation with the optic nerve head configuration than with age,
sex, or refractive error (9). The diameter and the area may vary depending on the definition of the edge
of the optic disc and methods of measurement (4, 10, 11). Therefore, some authors have suggested
applying various formulas to correct magnification of images when comparing disc measurements on
different instruments (12, 13).
The diameter of the nerve expands to approximately 3 mm just behind the sclera, where the neurons
acquire a myelin
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sheath. The optic nerve head is also the site of entry and exit of the retinal vessels. This vascular system
supplies some branches to the optic nerve head, although the predominant blood supply for the nerve
head comes from the ciliary circulation.
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Figure 4.1 A: Optic nerve head with physiologic enlarged cupping demonstrating robust, symmetric, and
healthy RNFL. B: Glaucomatous optic nerve showing an inferotemporal notch and corresponding loss of
the RNFL that is appreciated by “baring” of the retinal vessels. The point of the (arrows) delimits the
RNFL defect.
Figure 4.2 Divisions of the optic nerve head. A: Surface nerve fiber layer. B: Prelaminar region. C:
Lamina cribrosa region. D: Retrolaminar region.
Divisions of the Optic Nerve Head
The nerve head may be arbitrarily divided into four portions from anterior to posterior (14) (Fig. 4.2).
Surface Nerve Fiber Layer
The innermost portion of the optic nerve head is composed predominantly of nerve fibers. In the rhesus
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monkey, this layer is 94% RGC axons and 5% astrocytes (15). The axonal bundles acquire progressively
more interaxonal glial tissue in the intraocular portion of the nerve head as this structure is followed
posteriorly (15).
Prelaminar Region
The prelaminar region is also called the anterior portion of the lamina cribrosa (16). The predominant
structures at this level are nerve axons and astrocytes, with a significant increase in the quantity of
astroglial tissue.
Lamina Cribrosa Region
This portion contains fenestrated sheets of scleral connective tissue and occasional elastic fibers.
Astrocytes separate the sheets and line the fenestrae (16), and the fascicles of neurons leave the eye
through these openings.
Retrolaminar Region
This area is characterized by a decrease in astrocytes and the acquisition of myelin that is supplied by
oligodendrocytes. The axonal bundles are surrounded by connective tissue septa.
The posterior extent of the retrolaminar region is not clearly defined. An India ink study of monkey eyes
showed nonfilling with the ink for 3 to 4 mm behind the lamina cribrosa when the IOP was elevated
(17). However, a similar study using unlabeled microspheres showed an increased blood flow in the
retrolaminar region close to the lamina even when the IOP was elevated high enough to stop retinal
blood flow (18).
Vasculature
Arterial Supply
Posterior ciliary artery circulation is the main source of blood supply to the optic nerve head (19), except
for the nerve fiber layer—which is supplied by the retinal circulation. The blood supply in the optic
nerve head has a sectoral distribution (20). The four divisions of the optic nerve head correlate roughly
with a four-part vascular supply (Fig. 4.3).
The surface nerve fiber layer is mainly supplied by arteriolar branches of the central retinal artery, which
anastomose with vessels of the prelaminar region and are continuous with
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the peripapillary retinal and long radial peripapillary capillaries (14, 19, 21). The temporal region may
also be supplied by one or more of the ciliary-derived vessels from the posterior ciliary artery circulation
in the deeper prelaminar region, which may occasionally enlarge to form cilioretinal arteries (14). The
cilioretinal artery, when present, usually supplies the corresponding sector of the surface layer (20). In
elderly rhesus monkeys, central retinal artery occlusion for less than 100 minutes produced no apparent
evidence of optic nerve damage. However, longer occlusion produced a variable degree of damage (22).
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Figure 4.3 Vascular supply of the optic nerve head. CRA, central retinal artery; RPC, radial peripapillary
capillaries; PV, pial vessels; SPCA, short posterior ciliary arteries; PCV, peripapillary choroidal vessels;
ZH, “circle” of Zinn—Haller.
The prelaminar and laminar regions are supplied primarily by short posterior ciliary arteries, which form
a perineural, circular arterial anastomosis at the scleral level, called the circle of Zinn-Haller (14, 19, 21,
23). Branches from this circle penetrate the optic nerve to supply the prelaminar and laminar regions and
the peripapillary choroid (19). The circle is not present in all eyes, in which case direct branches from
the short posterior ciliary arteries supply the anterior optic nerve. The peripapillary choroid may also
minimally contribute to anterior optic nerve (14, 19, 21, 23).
The retrolaminar region is supplied by both the ciliary and retinal circulations, with the former coming
from recurrent pial vessels. Medial and lateral perioptic nerve short posterior ciliary arteries anastomose
to form an elliptical arterial circle around the optic nerve, which has also been referred to as the circle of
Zinn-Haller (24, 25). This perioptic nerve arteriolar anastomosis, which supplies the retrolaminar optic
nerve, was found to be complete in 75% of 18 human eyes in one study (24). The central retinal artery
provides centripetal branches from the pial system and frequently, but not always, gives off centrifugal
vessels (20).
Continuity between small vessels from the retrolaminar region to the retinal surface has been observed
(21), and the optic nerve head microvasculature is said to represent an integral part of the retina-optic
nerve vascular system (23).
Capillaries
Although derived from both the retinal and ciliary circulations, the capillaries of the optic nerve head
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resemble more closely the features of retinal capillaries than of the choriocapillaris. These characteristics
include (a) tight junctions, (b) abundant pericytes, and (c) nonfenestrated endothelium (23). They do not
leak fluorescein and may represent a nerve-blood barrier, supporting the concept of the retina-nerve
vasculature as a continuous system with the central nervous system (21, 23). The capillaries decrease in
number posterior to the lamina, especially along the margins of the larger vessels (26).
Venous Drainage
The venous drainage from the optic nerve head is almost entirely through the central retinal vein (19),
although a small portion may occur through the choroidal system (27). Occasionally, these
communications are enlarged as retinociliary veins, which drain from the retina to the choroidal
circulation, or cilio-optic veins, which drain from the choroid to the central retinal vein (28).
Astroglial Support
Astrocytes provide a continuous layer between the nerve fibers and blood vessels in the optic nerve head
(29). In the rhesus monkey, astrocytes occupy 5% of the nerve fiber layer, increase to 23% of the
laminar region, and then decrease to 11% in the retrolaminar area (15). The astrocytes are joined by
“gap junctions,” which resemble tight junctions but have minute gaps between the outer membrane
leaflets (30).
Thick- and thin-bodied astrocytes have been described. The thin-bodied astrocytes accompany the axons
in the nerve fiber layer, and the thick-bodied astrocytes direct axons in the prelaminar region toward the
laminar region (31).
The astroglial tissue also provides a covering for portions of the optic nerve head (Fig. 4.4). The internal
limiting membrane of Elschnig separates the nerve head from the vitreous and is continuous with the
internal limiting membrane of the retina (29, 32, 33 and 34). The central portion of the internal limiting
membrane is referred to as the central meniscus of Kuhnt (33). Although the central meniscus of Kuhnt
is traditionally described as a central thickening of the internal limiting membrane, ultrastructural studies
of the monkey optic nerve head revealed a thinning of 20 nm centrally, which thickened to 70 nm
peripherally (34). The Müller cells are a major constitutional element of the intermediary tissue of Kuhnt
(35), which separates the nerve from the retina, whereas the border tissue of Jacoby separates the nerve
from the choroid (16, 33).
Astrocytes also play a major role in the remodeling of the extracellular matrix of the optic nerve head
and synthesizing growth factors and other cellular mediators that may affect the axons of the RGCs and
contribute to health or susceptibility to disease (36).
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Figure 4.4 Supportive structures of the optic nerve head: internal limiting membrane of Elschnig (a);
continuous with the internal limiting membrane of the retina (b); central meniscus of Kuhnt (c);
intermediary tissue of Kuhnt (d); border tissue of Jacoby (e); border tissue of Elschnig (f); lamina
cribrosa (g); meningeal sheaths (h).
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Connective Tissue Support
Lamina Cribrosa
This structure is not simply a porous region of the sclera but also a specialized extracellular matrix that
consists of fenestrated sheets of connective tissue and occasional elastic fibers lined by astrocytes (16,
37). Astrocytes may respond to changes in IOP in glaucoma, leading to axonal loss and RGC
degeneration at the level of lamina cribrosa (36). Extracellular matrix components in the lamina cribrosa
differ from those in sclera or pial septa (38), which may be important in the pathogenesis of
glaucomatous optic nerve damage. Hyaluronate was found surrounding the myelin sheaths in the
retrolaminar nerve, playing an important role in the maintenance of the hydrodynamic properties of the
extracellular matrix. Hyaluronate decreases with age and is further reduced in eyes with chronic openangle glaucoma (COAG), possibly increasing susceptibility to elevated IOP (39). The lamina cribrosa
has also been found to be significantly thinner in glaucomatous eyes than in nonglaucomatous eyes (40).
Analysis of the pores in the lamina cribrosa with a confocal scanning laser ophthalmoscope shows
nearly round pores in the eyes with physiologic cupping, whereas eyes with COAG frequently have
compressed pores (41). There are regional differences in the fenestration or pores through which the
axons pass. The superior and inferior portions, compared with the nasal and temporal regions, have
larger single pore areas and summed pore areas and thinner connective tissue and glial cell support (42,
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43, 44 and 45) (Fig. 4.5). The ratio of single and summed pore areas between the laminar regions
decreases with increasing lamina cribrosa area, but does not correlate with age or sex (45). A majority of
RGC axons take a direct course through the lamina cribrosa (46), but about 10% of axons exit more
peripherally, where the lamina cribrosa is more curvilinear, which may influence the regional
susceptibility for glaucomatous optic nerve fiber loss (47). The size of the laminar openings for the
retinal vessels does not correlate with the lamina cribrosa area (45).
Figure 4.5 Gross anatomic photograph of lamina cribrosa showing central openings for central retinal
vessels (arrow) and surrounding fenestrae of lamina for passage of axon bundles. Note larger size of
fenestrae in superior and inferior quadrants. S, superior; T, temporal. (Courtesy of Harry A. Quigley,
MD.)
As mentioned previously, the lamina cribrosa of the human optic nerve head contains a specialized
extracellular matrix composed of collagen types I through VI, laminin, and fibronectin (48, 49 and 50).
Studies of young human donor eyes show that the cribriform plates are composed of a core of elastin
fibers with a sparse, patchy distribution of collagen type III, coated with collagen type IV and laminin
(48). Cell cultures of human lamina cribrosa reveal two cell types, which appear to synthesize this
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extracellular matrix (51). The expression of mRNA for collagen types I and IV in both fetal and adult
human optic nerve heads suggests that these extracellular matrix proteins are synthesized in this tissue
throughout life (52). Proteoglycans, which are macromolecular components of connective tissue
believed to have a role in the organization of other extracellular matrix components and in the hydration
and rigidity of tissue, have been identified in the cores of the laminar plates in association with collagen
fibers (53, 54). Cell adhesive proteins, including vitronectin and thrombospondin, have been found in
human lamina cribrosa (38). Abnormalities of this extracellular matrix in the lamina cribrosa may
influence optic nerve function and its susceptibility to glaucomatous damage caused by elevated IOP.
Lamina cribrosa cells from glaucomatous eyes express more profibrotic genes than cells from normal
lamina cribrosa do (55). These differences in extracellular matrix probably translate into difference in
biomechanical properties (56, 57).
Nerve Sheaths
A rim of connective tissue, the border tissue of Elschnig, occasionally extends between the choroid and
optic nerve tissues, especially temporally (33) (Fig. 4.4). Posterior to the globe, the optic nerve is
surrounded by meningeal sheaths (pia, arachnoid, and dura), which consist of connective tissue lined by
meningothelial cells, or mesothelium (58). Lymphatic capillaries in the dura of the human optic nerve
have been described (59). Vascularized connective tissue extends from the undersurface of the pia mater
to form longitudinal septa, which partially separate the axonal bundles in the intraorbital portion of the
optic nerve (33).
Axons
Retinal Nerve Fiber Layer
As the axons traverse the nerve fiber layer from the ganglion cell bodies to the optic nerve head, they are
distributed in a characteristic pattern (Fig. 4.6). Fibers from the temporal periphery originate on either
side of a horizontal dividing line, the median raphe, and arch above or below the fovea as the arcuate
nerve fibers, while those from the central retina, the
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papillomacular fibers, and the nasal fibers take a more direct path to the nerve head. The significance of
this anatomy to the visual field defects of glaucoma is discussed in Chapter 5. The axons in monkeys
and rabbits are grouped into fiber bundles by tissue tunnels composed of elongated processes of Müller
cells (60, 61 and 62). These bundles, especially on the temporal side, become larger as they approach the
nerve head, primarily because of lateral fusion of bundles (63), and are normally visible by
ophthalmoscopy as retinal striations (62). The axons in the bundles vary in size, with larger fibers
coming from the more peripheral retina (63). One study also demonstrated that intra-RGC axons contain
numerous bulb-shaped varicosities in humans of different ages (64).
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Figure 4.6 Distribution of retinal nerve fibers. Note arching above and below the fovea of fibers
temporal to the optic nerve head. Inset depicts crosssectional arrangement of axons, with fibers
originating from peripheral retina running closer to choroid and periphery of optic nerve, while fibers
originating nearer to the nerve head are situated closer to the vitreous and occupy a more central portion
of the nerve.
Axons in Optic Nerve Head
The arcuate nerve fibers occupy the superior and inferior temporal portions of the optic nerve head, with
axons from the peripheral retina taking a more peripheral position in the nerve head (Fig. 4.6) (65). The
arcuate fibers are the most susceptible to early glaucomatous damage. The papillomacular fibers spread
over approximately one third of the distal optic nerve, primarily inferior temporally, where the axonal
density is higher (66, 67). They intermingle with extramacular fibers, which may explain the retention of
central vision in early glaucomatous optic atrophy.
The mean axonal population in the normal human optic nerve head, as measured by computed image
analysis of sections throughout the nerve, ranges from approximately 700,000 fibers to 1.2 million fibers
(67, 68, 69 and 70). The optic nerve fiber count has been shown to increase significantly with the optic
nerve head area in human and monkey eyes, although another study of human eyes showed no such
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correlation (69, 71, 72). A positive correlation has also been demonstrated between the retinal
photoreceptor count and optic nerve area (73). The reported mean axonal fiber diameter ranges from
0.65 to 1.10 µm (67, 68, 74). Axons of all sizes are mixed throughout the nerve area, although higher
mean diameters appear to be more common in the nasal segment (67).
EMBRYOLOGY OF THE RETINA AND OPTIC NERVE
The retina and optic nerve develop from the optic cup and the contiguous optic stalk (75, 76, 77, 78, 79
and 80).
The inner layer of the cup contains the pluripotent retinal progenitor cells, which differentiate in a
specific chronologic sequence and defined histogenic order into the final seven retinal cell types (see
Fig. 1.3 in Chapter 1). In general, the RGCs differentiate first (81, 82), followed by the cone
photoreceptors, amacrine cells, horizontal cells, and finally, the rod photoreceptors, bipolar cells, and
Müller cells. Retinal neurogenesis starts in the central optic cup region and then fans out concentrically
in a wavelike pattern into the periphery. There is a basic topographic organization of the optic cup with
dorsoventral and nasotemporal patterning (83), which involves certain genetic cues, including that of the
Otx genes (84).
The optic fissure of the optic stalk closes to convert it into a cylinder, into which the RGC axons grow.
The lumen of the
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optic stalk is obliterated by axons by approximately the third fetal month. Apoptosis, or selective cell
death, and cell cycle regulators are important in normal ocular development (85, 86 and 87). The optic
nerve axon count in humans peaks at approximately 3.7 million by fetal week 16 to 17 and then rapidly
declines to near adult levels of around 1 million by term (88). Epithelial cells in the walls of the stalk
differentiate into the neuroglia of the optic nerve. Mesenchymal tissue gives rise to the optic nerve septa
in the third month and to the lamina cribrosa in the final month of gestation.
Key regulatory genes involved in the early development of the eye and the fate of retinal cells include
Pax6, Rxl, Six3/6, Lhx2, and certain basic helix-loop-helix transcription factors. The expression of these
genes and their effect on retinal neurogenesis and differentiation are considered “cell-intrinsic”
mechanisms, whereas “extrinsic” mechanisms include thyroid hormones and their receptors, fibroblast
growth factors and other “growth factors,” hedgehog proteins, various neurotrophins, and nitric oxide
(75, 89, 90, 91, 92, 93, 94 and 95).
The optic nerve cross-sectional area reaches 50% of the adult size by 20 weeks' gestation, 75% at birth,
and 95% before 1 year of age (96). At birth, the optic nerve is nearly unmyelinated (97), and
myelination, which proceeds from the brain to the eye during gestation, is largely completed in the
retrolaminar region of the optic nerve by the first year of life (98). The connective tissue of the lamina
cribrosa is also incompletely developed at birth, which may account for the increased susceptibility of
the infant nerve head to glaucomatous cupping and its potential for reversible cupping (99). With
increasing age, the cores of the cribriform plates enlarge, and the apparent density of collagen types I,
III, and IV and elastin increases (100, 101). Not only does elastin increase with age, but also elastic
fibers become thicker, tubular, and surrounded by densely packed collagen fibers (101). Proteoglycan
filaments in the human lamina cribrosa also decrease in length and diameter with age (102). Also with
increasing age, there appears to be a progressive loss of axons with a decrease of the nerve fiber layer
thickness (103, 104) and a corresponding increase in the cross-sectional area occupied by the
leptomeninges and fibrous septa (67, 68, 69 and 70). The loss of axons has been estimated to be between
4000 and 12,000 per year, with most studies nearer the lower figure (67, 69, 70, 105). One study
suggested a selective loss of large nerve fibers with age (68), although this has not been confirmed by
others (67, 74).
PATHOPHYSIOLOGY OF GLAUCOMATOUS OPTIC NERVE DAMAGE
Theories
The pathogenesis of glaucomatous optic atrophy has remained a matter of controversy since the mid19th century, when two concepts were introduced in the same year. In 1858, Müller (106) proposed that
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the elevated IOP led to direct compression and death of the neurons (the mechanical theory), while von
Jaeger (107) suggested that a vascular abnormality was the underlying cause of the optic atrophy (the
vascular theory). In 1892, Schnabel (108) proposed another concept in the pathogenesis of glaucomatous
optic atrophy, suggesting that atrophy of neural elements created empty spaces, which pulled the nerve
head posteriorly (Schnabel cavernous atrophy).
Initially, the mechanical theory received the greatest support (109, 110 and 111). This concept held sway
through the first quarter of the 20th century until LaGrange and Beauvieux (112) popularized the
vascular theory in 1925. In general, this belief held that glaucomatous optic atrophy was secondary to
ischemia, whether the primary result of the elevated IOP or an unrelated vascular lesion (113, 114 and
115). In 1968, however, the role of axoplasmic flow in glaucomatous optic atrophy was introduced
(116), which revived support for the mechanical theory, but did not exclude the possible influence of
ischemia.
Evidence
Continued investigation into the pathogenesis of glaucomatous optic atrophy has led to the following
bodies of information.
Anatomic and Histopathologic Studies
Histopathologic observations of human eyes with glaucoma provide the most direct method of studying
the alterations associated with glaucomatous optic atrophy, although they do not fully explain the
mechanisms that caused the damage. One of the limiting factors has been that many of the specimens
studied have come from eyes with advanced glaucomatous change, which led to possible
misconceptions regarding the early pathogenic features. More recent studies, which have attempted to
correlate clinical observations with histopathologic changes in optic nerve heads from eyes with varying
stages of glaucoma, appear to clarify many of these points.
Glial Alterations
It was once suggested that loss of astroglial supportive tissue precedes neuronal loss (117), which was
thought to explain the early and reversible cupping in infants (118). However, subsequent studies have
shown that glial cells are not selectively lost in early glaucoma and are actually the only remaining cells
after loss of axons in advanced cases (119, 120).
Vascular Alterations
It was also once proposed that loss of small vessels in the optic nerve head accompanies atrophy of
axons (121), and one histologic study suggested a selective loss of retinal radial peripapillary capillaries
in eyes with chronic glaucoma (122). However, subsequent investigations revealed neither a correlation
between atrophy of this vascular system and visual field loss nor a major selective loss of optic nerve
head capillaries in human eyes with glaucoma (119, 120, 123, 124). In animal models of optic atrophy,
created by either sustained IOP elevation, sectioning of the optic nerve, or photocoagulation of the
RNFL, the resulting disc pallor was not associated with a decrease in the ratio of capillaries to neural
tissue, although the caliber of the vessels diminished (124, 125, 126, 127 and 128). Instead, these studies
showed a proliferation or reorganization of glial tissue, which obscures ophthalmoscopic visualization of
the vessels (125, 126, 128).
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Alterations of the Lamina Cribrosa
Backward bowing of the lamina cribrosa has long been recognized as a characteristic feature of late
glaucomatous optic atrophy (129, 130), and as an early change in the infant eye with glaucoma (99).
Further study, however, has suggested that alterations in the lamina may actually be a primary event in
the pathogenesis of glaucomatous optic atrophy. In enucleated human eyes, acute IOP elevation causes a
backward bowing of the lamina (131, 132), and similar changes are observed in primate glaucoma
models (133, 134) with compensatory remodeling and fibrosis (135).
Most of the posterior displacement occurred in the peripheral lamina cribrosa, corresponding to the
region of early axonal loss (132). In a histopathologic evaluation of 25 glaucomatous human eyes,
compression of successive lamina cribrosa sheets was the earliest detected abnormality, and backward
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bowing of the entire lamina occurred later and involved primarily the upper and lower poles (136).
In the early stages of adult glaucoma, the magnitude of backward bowing is not sufficient to explain the
ophthalmoscopically observed cupping, but may be enough to produce a pressure gradient along the
axoplasm of exiting optic nerve axons, compromise the circulation (137), and cause compression of the
axons. It has been suggested that the structure of the lamina cribrosa may be an important determinant in
the susceptibility of the optic nerve head to damage from elevated IOP (119, 120). However, racial
comparison of the relative connective tissue support and regional pore size of the lamina cribrosa did not
explain the increased susceptibility of blacks to glaucomatous damage (138). The extracellular matrix of
the lamina cribrosa may play an important role in the progression of glaucomatous damage (139, 140
and 141). In glaucomatous monkey eyes, increased collagen type IV and laminin lined the margins of
the laminar beams (140, 141), and collagen types I, III, and IV were found in the pores of the beams
(140). Elastin, which is the major protein of elastic fibers and responsible for elastic recoil, appeared
curled instead of straight and seemed disconnected from other elements of the connective tissue matrix
in glaucomatous eyes of humans and monkeys (142). Elastin mRNA expression in human eyes with
COAG suggests synthesis of abnormal elastic fibers (143). These changes may be secondary to longstanding elevation of IOP and may modify the course of glaucomatous optic atrophy.
Figure 4.7 A: Light microscopic view of normal optic nerve head on cross section with darkly staining
axon bundles and intervening glial supportive tissue surrounding openings for central retinal vessels. B:
Light microscopic cross-sectional view of optic nerve head with glaucomatous atrophy showing loss of
axon bundles predominantly in the inferior and superior quadrants (compare with normal nerve head in
A). INF, inferior; NAS, nasal; SUP, superior; TEM, temporal. (Courtesy of Harry A. Quigley, MD.)
Axonal Alterations
The actual cause of early optic nerve head cupping in glaucoma appears to be the loss of axonal tissue
(119, 120, 144). Experimental models of primate eyes exposed to chronic IOP elevation suggest that the
damage is associated with a posterior and lateral displacement of the lamina cribrosa, which compresses
the axons and disrupts axoplasmic flow (145). The damage first involves axonal bundles throughout the
nerve with somewhat greater involvement of the inferior and superior poles (136). With continued optic
nerve damage, the susceptibility of the polar zones becomes more prominent (Fig. 4.7) (119, 120, 136,
144). Histologic studies of both monkey and human optic nerves indicate that nerve fibers larger than
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the normal mean diameter atrophy more rapidly in glaucomatous eyes, although no fiber size is spared
from damage (146, 147). This preferential loss of large fibers appears to be due to a higher proportion of
the fibers in
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the inferior and superior poles, and an inherent susceptibility to injury by glaucoma (146, 147).
In the retina of glaucomatous monkey eyes, there is also a selective loss of the larger ganglion cells in
both the midperiphery and fovea, and it has been suggested that psychophysical testing should be aimed
at these cells in the early stages of glaucoma (148, 149). The same animal studies suggest that RGCs in
glaucoma die by apoptosis, a genetically programmed process of cell death, characterized histologically
by chromatin condensation and intracellular fragmentation (150). This apoptosis is possibly related to
loss of trophic influences resulting from inhibited transmission of neurotrophic signals from axon
terminals to neuronal cell bodies; histologic studies have also shown a significant decrease of corpora
amylacea, which are homogeneous oval bodies believed to correlate with axonal degeneration, in RGCs
and the optic nerve of human eyes with advancing stages of glaucoma (151, 152). One study revealed a
significant reduction in photoreceptor count in human eyes with angle-closure glaucoma associated with
trauma (153), although this was not observed in human eyes with COAG or in monkey eyes with
experimental glaucoma (154, 155).
Secondary degeneration has been reported to occur after experimental injury of RGCs, causing loss of
neighboring RGCs as an indirect effect of the injury and death of transected RGCs. Glutamate levels in
the vitreous did not increase at 3 months after injury, suggesting the need for further investigations of
the mechanisms of secondary degeneration (156).
Blood-Flow Studies
Blood flow in the optic nerve head of cats is relatively high compared with that in more posterior
portions of the nerve, and autoregulation appears to compensate for alterations in mean arterial blood
pressure (157). With elevation of IOP, blood flow in the optic nerve head, retina, and choroid of cat eyes
is only slightly affected before the pressure is within 25 mm Hg of the mean arterial blood pressure, and
flow in the lamina cribrosa is reduced only with extreme pressure elevations, again suggesting
autoregulation in the optic nerve head (158). Another study, however, suggests that the electrical
function of ganglion cell axons in cat eyes depends on the perfusion pressure and not on the absolute
height of the IOP (159). Real-time analysis of optic nerve head oxidative metabolism in cats indicates
that the metabolic response is dependent on IOP or mean arterial pressure and that lowering the IOP can
reverse metabolic dysfunction (160).
Short-term IOP elevation in monkey eyes did not alter optic nerve head blood flow until it exceeded 75
mm Hg, and longterm glaucoma in monkeys had no apparent influence on mean blood flow in the nerve
head (161); others have shown that the threshold of IOP that is needed to affect blood flow is partly
determined by the animal's systemic blood pressure (162). A study of oxygen tension in the monkey
optic nerve head suggested that autoregulation compensates for changes in perfusion pressure (163), and
a noninvasive phosphorescence imaging technique in cats revealed well-maintained oxygen tension in
the optic nerve head and retina despite increasing IOP, until blood flow to the eye was stopped (164).
Blood-flow measurements in the optic nerve head of human eyes, using laser Doppler, demonstrate
autoregulatory compensation to reduced perfusion pressure secondary to elevated IOP (165). In
glaucomatous eyes, however, Doppler studies show reduced flow velocity in the nerve head (166, 167,
168 and 169). Blood flow of the optic nerve head lamina, rim area, and retrobulbar flow is decreased
with increasing glaucomatous damage (170, 171). Eyes with glaucoma also appear to have more diurnal
fluctuation of optic nerve blood flow (172).
A technique of continuously monitoring disc brightness during and after an abrupt artificial elevation of
IOP also showed that the extent to which a glaucomatous eye can adjust to the pressure changes is
significantly reduced from that of nonglaucomatous eyes (173). Diminished autoregulatory response to
postural changes in the retinal vasculature of patients with glaucoma is also seen (174). Age may
influence the vascular responses to IOP. One study showed that major retinal vessels at the disc border
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increased in caliber in response to IOP reduction in patients with COAG who were 55 years or younger,
but not after that age (175). In children, intracranial pressure also affects optic nerve blood flow (176). It
may be that ischemia of the optic nerve head in glaucoma involves faulty autoregulation, which may
worsen with age and is also affected by systemic blood pressure and intracranial blood pressure (158,
177, 178). Molecules such as endothelin and nitric oxide are being investigated for their possible role in
the normal and altered autoregulatory responses (179, 180).
Fluorescein Angiography
Normal Fluorescein Pattern
The normal fluorescein pattern of the optic nerve head is usually described as having three phases (14):
In the first phase, an initial filling, or preretinal arterial, phase is thought to represent filling of the
prelaminar and lamina cribrosa regions by the posterior ciliary arteries. Fluorescein in the retrobulbar
vessels may also contribute to this phase (181).
The peak fluorescence, or retinal arteriovenous phase, is primarily due to filling of the dense capillary
plexus on the nerve head surface from retinal arterioles. With increasing age, there is a decrease in the
filling time of both the retinal and choroidal circulations (182).
A late phase consists of 10 to 15 minutes of delayed staining of the nerve head, probably because of
fluorescein in the connective tissue of the lamina cribrosa. Tracer studies in monkeys suggest that the
leakage may come from the adjacent choroid (183).
Effect of Artificially Elevated IOP
The effect of artificially elevated IOP on the fluorescein angiographic pattern has provided an
understanding of the relative vulnerability of ocular vessels to elevated pressure in the normal and
glaucomatous eyes. There is a general delay in the entire ocular circulation in response to an elevation of
the IOP. The prelaminar portion of the nerve head appears to be the most vulnerable portion of the
ocular vascular system to elevated pressure in monkeys (14, 184).
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Studies regarding the vulnerability of the peripapillary choroid to IOP elevation have provided
conflicting results. Fluorescein angiography of monkey eyes has suggested a marked susceptibility of
this vascular system to elevated pressure (14, 184), and fluorescein studies of human eyes with
glaucoma have shown similar delays in peripapillary choroidal filling (184, 185, 186, 187, 188). The
delay appears to be sensitive to elevated IOP (185). It has been suggested that this vascular disturbance
of the peripapillary choroid contributes to glaucomatous optic atrophy (187). However, fluorescein
angiographic studies of normal human eyes have shown similar delayed or irregular choroidal filling at
normal pressures (189, 190), and the peripapillary choroidal capillaries of normal human eyes were
relatively resistant to artificial pressure elevations (191). Furthermore, a fluorescein study of patients
with low-tension glaucoma or COAG provided no evidence that hypoperfusion of the peripapillary
choroid contributed to optic nerve hypoperfusion (192).
A selective nonfilling of the retinal radial peripapillary capillaries during India ink perfusion has been
demonstrated in cats (193). As previously discussed, however, histopathologic observations differ
regarding alterations of this vascular system in glaucomatous eyes (122, 123). Most studies of monkey
and normal human eyes have shown the choroidal circulation in general to be more vulnerable than that
of the retina to elevated IOP (14, 184, 187, 194), although one study found the two systems to fill at the
same level of increased pressure (195). Regional differences in circulation of the optic nerve head,
retina, and peripapillary choroid have been reported (196).
Studies of Glaucomatous Eyes
Fluorescein angiographic studies of glaucomatous and nonglaucomatous eyes have revealed two types
of filling defects of the optic nerve head: (a) persisting hypoperfusion and (b) transient hypoperfusion
(192, 197).
Persisting hypoperfusion, or absolute filling defects, is more common in eyes with glaucoma, especially
low-tension glaucoma, and are said to correlate with visual field loss (192, 197, 198). The characteristics
of a filling defect include decreased blood flow, a smaller vascular bed, narrower vessels, and increased
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permeability of the vessels (199). The filling defect may be either focal or diffuse. The former is thought
to reflect susceptible vasculature with or without elevated IOP, and is the typical defect in low-tension
glaucoma (192). Focal defects occur primarily in the inferior and superior poles of the optic nerve head
(197, 198, 200). In glaucomatous eyes, they are most often seen in the wall of the cup, whereas in
nonglaucomatous eyes they occur more commonly in the floor of the cup (201). The diffuse defect is
thought to represent prolonged pressure elevation (192).
The nature of the defect in COAG is thought to be specific, and fluorescein angiography of the optic
nerve head may help to differentiate COAG from other conditions that have similar clinical changes in
the optic disc (202). Computed image analysis has been used to objectively quantify fluorescein
angiograms of the optic disc and has shown that increases in fluorescein-filling defect areas correlate
with glaucomatous progression (203).
In patients with low-tension glaucoma, retinal arteriovenous passage times are prolonged in fluorescein
angiography, possibly from the increased resistance in the central retinal and posterior ciliary arteries.
Arteriovenous passage correlated with the size of the optic nerve head, visual field indices, and contrast
sensitivity (204).
Axoplasmic Flow
Physiology of Axoplasmic Flow
Axoplasmic flow, or axonal transport, refers to the movement of material (axoplasm) along the axon of a
nerve (the dendrite may also have transport) in a predictable, energy-dependent manner. This movement
has been characterized as having fast and slow components, although numerous intermediate rates may
also exist (205). The fast phase moves approximately 410 mm/day in various species and may supply
material to synaptic vesicles, the axolemma, and agranular endoplasmic reticulum of the axon; the slow
phase moves at 1 to 3 mm/day and is believed to subserve growth and maintenance of axons (205). The
flow of axoplasm may be orthograde (from retina to lateral geniculate body) or retrograde (lateral
geniculate body to retina) (206).
Experimental Models of Axoplasmic Flow
Animal models (usually in monkeys) have been developed for studying axoplasmic flow by injecting
radioactive amino acids, such as tritiated leucine, into the vitreous. In other animal models, the results
may have less generalizability to human glaucoma because of species differences of the lamina cribrosa
region; some animals do not have a lamina. The amino acid is incorporated into the protein synthesis of
RGCs and then moves down the ganglion cell axon into the optic nerve, allowing histologic study of the
orthograde movement of radioactively labeled protein (207). In addition, retrograde flow can be studied
by observing the accumulation of certain unlabeled neuronal components, such as mitochondria by
electron microscopy (208), or by injecting tracer elements, such as horseradish peroxidase into the
lateral geniculate body and studying its movement toward the retina (209). These models can be used to
study factors that cause abnormal blockade of axoplasmic flow, which may relate to glaucomatous optic
atrophy in the human eye.
Influence of IOP on Axoplasmic Flow
Elevated IOP in monkey eyes causes obstruction of axoplasmic flow at the lamina cribrosa and the edge
of the posterior scleral foramen (206, 210, 211, 212, 213, 214 and 215). Axonal transport in monkey
eyes with chronic IOP elevation is also preferentially decreased in the magnocellular layers of the dorsal
lateral geniculate nucleus, to which the large RGCs project (216). The obstruction in general involves
both the fast and slow phases, and the orthograde and retrograde components (206, 211, 213, 214). In
monkey eyes, the obstruction to fast axonal transport preferentially involves the superior, temporal, and
inferior portions of the optic nerve head (217). The height and duration of pressure elevation influence
the onset, distribution, and degree of axoplasmic obstruction in the optic nerve head (214, 218, 219).
The mechanism by which elevated IOP leads to obstruction of axoplasmic flow is uncertain, but there
are two popular theories: mechanical and vascular.
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The mechanical theory suggests that physical alterations in the optic nerve head lead to misalignment of
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the fenestrae in the lamina cribrosa and may result in axoplasmic flow obstruction (116, 130, 214). In
support of this hypothesis is the observation that elevated IOP leads to blockage of axonal transport
despite an intact nerve head capillary circulation and an elevated arterial pO2 (206, 220). Furthermore,
obstruction of axoplasmic flow has also been reported in response to ocular hypotony (211, 213, 221),
leading some investigators to suggest that a pressure differential across the optic nerve head, whether
due to a relative increase or decrease in IOP, causes mechanical changes with compression of the axonal
bundles (211, 213, 221, 222). In the laminar portion of pig ganglion cell axons, cytoskeletal changes are
seen before disruption of axoplasmic flow; the disruption of axoplasmic flow was observed to be greater
in the axons of the periphery of the optic nerve, favoring a mechanical issue as the primary pathologic
process (223).
In conflict with the mechanical theory is the observation that elevated intracranial pressure in monkeys
neither caused obstruction of rapid axoplasmic flow nor prevented it in response to elevated IOP, despite
reduction in the pressure gradient across the lamina (224). This suggests that more than a simple
mechanical or hydrostatic mechanism may be involved with obstruction of axoplasmic flow in response
to elevated IOP (224). Also against the simple mechanical theory are the observations that axon damage
is diffuse within bundles, rather than focal, as might be expected with a kinking effect (225), and the
location of transport interruption does not correlate with the cross-sectional area of fiber bundles, the
shape of the laminar pores, or the density of interbundle septa (226, 227).
The vascular theory suggests that ischemia at least plays a role in the obstruction of axoplasmic flow in
response to elevated IOP. Interruption of the short posterior ciliary arteries in monkeys has been
reported to block both slow and fast axoplasmic flow, although it did not cause glaucomatous cupping
(228, 229,and 230). Central retinal artery occlusion has been associated with obstruction of rapid
orthograde and retrograde axonal transport (231). Furthermore, accumulation of tracer at the lamina
cribrosa was inversely proportional to the perfusion pressure in cat eyes (232), and IOP-induced
blockage of axonal transport was increased in eyes with angiotensin-induced systemic hypertension
(233). In monkey eyes with elevated IOP, leakage from microvasculature of the nerve head has been
associated with blockade of axonal transport at the lamina cribrosa (234).
Arguing against a vascular mechanism for pressure-induced obstruction of axoplasmic flow is the
observation that ligation of the right common carotid artery in monkeys, which reduced the estimated
ophthalmic artery pressure by 10 to 20 mm Hg, does not significantly affect the extent to which IOP
elevation interrupts axonal transport (235). When obstruction to retrograde axoplasmic flow was studied
in rat eyes, a direct relationship with IOP was still found, although the influence of the blood circulation
was removed and the lamina cribrosa is only a single laminar sheet (209). It may be, therefore, that
factors other than, or in addition to, ischemia and kinking of axons by a multilayered lamina cribrosa are
involved in the IOP-induced obstruction to axoplasmic flow.
One study has found that partial constriction of axoplasmic flow may be present at the lamina cribrosa in
orthograde and retrograde directions, and that accumulations of mitochondria at that level were more
common in unmyelinated axons than in adjacent, myelinated axons. The authors suggested that the
constriction may be a factor in glaucoma wherein IOP is not elevated (236). Endothelin-1, which
produces vasoconstriction, reduces fast axonal transport in rats (237).
The effects on axoplasmic flow in the laminar region that are seen in monkeys with experimental
glaucoma are similar to those seen in one of the few species to develop spontaneous glaucoma, the
American Cocker Spaniel (238).
Cerebrospinal Fluid Pressure and Glaucomatous Optic Neuropathy
Anatomically, the cerebrospinal fluid (CSF) extends anteriorly in the optic nerve sheath and the
subarachnoid space to the posterior aspect of the lamina cribrosa. Although IOP has been known to play
a role in glaucomatous optic neuropathy, only relatively recently has there been speculation about any
effect the CSF pressure may have (239, 240). Studies in dogs have shown that the biomechanical effect
of altering CSF pressure on the lamina cribrosa is equal to or greater than an equivalent change in IOP
(241). Studies of the optic nerve architecture in human eyes have shown that the lamina cribrosa is
relatively thin and bowed posteriorly in human eyes with glaucoma (40, 242) (Fig. 4.8). A recent
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retrospective study found that the CSF pressure in patients with COAG was significantly decreased
(243). In a subsequent study, CSF pressure was also lower in patients with normal-tension glaucoma and
higher in patients with ocular hypertension, compared with control participants (244). A prospective
study confirmed that persons with COAG have significantly lower CSF pressures than controls do; in
addition, CSF pressure was lower in patients with normal-tension glaucoma than in patients with COAG
(245). In this study, IOP, CSF pressure, and blood pressure were positively correlated, suggesting a
dynamic interplay among these factors. Although preliminary, these studies suggest that translaminar
pressure—the difference between IOP and CSF pressure—plays an important role in the pathogenesis of
glaucomatous optic neuropathy.
Electrophysiologic Studies
When the IOP is artificially elevated in healthy human eyes, a significant reduction in the amplitudes of
electroretinographic components and visual-evoked potentials occurs only when the pressure approaches
or exceeds the ophthalmic blood pressure (246, 247). However, the perfusion-pressure amplitude curve
of the visual-evoked potential in normal eyes showed a kink, suggestive of vascular autoregulation,
which was not observed in patients with glaucoma (248), again pointing to a possible deficiency in
autoregulation in glaucoma. As previously noted, the electrical function of RGCs in cat eyes was found
to depend more on perfusion pressure than the absolute height of the IOP (159).
The pattern electroretinography is believed to originate in the RGCs and is expected to be reduced in
glaucoma. Therefore, it might be used to detect ganglion cell loss, but it failed
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to separate glaucoma patients from healthy individuals when used alone (249). However, a study of
patients with ocular hypertension showed that pattern electroretinographic amplitude correlates with
various optic disc morphometric parameters, particularly in sectors considered to be at risk for early
glaucomatous damage (250). Although still early in its development, pattern electroretinography, as well
as multifocal electroretinography, shows promise in the roles of diagnosis and functional assessment of
ganglion cell loss (251, 252, 253 and 254).
Figure 4.8 A: Histologic section (PAS) of the optic nerve in a nonglaucomatous eye. The lamina
cribrosa is indicated. B: Histologic section of the optic nerve in a glaucomatous eye. Compared with A,
the lamina cribrosa is thinner and bowed posteriorly. Note the reduction in distance between the
subarachnoid space, containing cerebrospinal fluid, and the laminar tissues. (Reproduced from Jonas JB,
Berenshtein E, Holbach L. Anatomic relationship between lamina cribrosa, intraocular space, and
cerebrospinal fluid space. Invest Ophthalmol Vis Sci. 2003;44:5189-5195, with permission.)
Comparison with Nonglaucomatous Optic Atrophy
Studies of other ocular disorders provide some indirect insight into the possible mechanism of
glaucomatous optic atrophy. For example, a histopathologic study of severe peripapillary choroidal
atrophy revealed a normal optic nerve head, suggesting that the vascular supply of these two structures
may be independent (255). Studies of nonglaucomatous optic atrophy have been used both to support
and to refute an ischemic basis for glaucomatous optic atrophy. In patients with anterior ischemic optic
neuropathy, cupping similar to that seen in glaucoma is frequently observed when the ischemia is due to
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giant cell arteritis, but it is less common in nonarteritic cases (256, 257 and 258). These observations
have led to the suggestion that glaucoma and anterior ischemic optic neuropathy have the same
vasogenic basis of optic nerve damage, but differ according to the rate of change (256). It has also been
suggested that acute ischemic optic neuropathy may be one of several mechanisms of optic nerve
disease in chronic glaucoma (259). If this is true, the difference in visual field loss suggests that there is
also a difference in the nature or distribution of the ischemia (258). In addition, the pattern of optic nerve
fiber loss in nonarteritic anterior ischemia optic neuropathy involves primarily the superior half of the
nerve and is unlike that found in glaucoma (260).
In contrast to the studies already described, a review of 170 eyes with nonglaucomatous optic atrophy of
various etiologies revealed a small but significant increase in cupping (261). However, the cups were
morphologically different from those seen in glaucoma, which was suggested as evidence against a
vascular etiology in glaucomatous cupping. Furthermore, a study of 18 patients with vasogenic shock
and poor peripheral tissue perfusion revealed no evidence of glaucomatous optic nerve head or visual
field change (262).
Cavernous atrophy of the optic nerve, as originally described by Schnabel (108), has been considered to
be a form of glaucomatous optic atrophy caused by severe elevations of IOP. However, this also occurs
in patients with normal pressures, in which case it may represent an aging change associated with
generalized arteriosclerosis and a chronic vascular occlusive disease of the proximal optic nerve (263,
264).
Conclusions Regarding Pathophysiology
The present evidence suggests that obstruction to axoplasmic flow may be involved in the pathogenesis
of glaucomatous optic atrophy. However, it is still unclear whether mechanical or vascular factors are
primarily responsible for this obstruction, or whether other alterations are also important in the ultimate
loss of axons. All of these factors may be involved to some degree, or there may be more than one
mechanism of optic atrophy in eyes with glaucoma (197, 265). For example, the observed differences in
glaucomatous visual field defects between patients with low-tension and high-tension glaucomas have
led to the suggestion that ischemia may be the predominant factor in those glaucomas at the lower end of
the IOP scale, whereas a more direct mechanical effect of the pressure may prevail in cases with higher
IOP (266).
CLINICAL APPEARANCE OF OPTIC NERVE HEAD
While investigators continue to study the pathophysiology of glaucomatous optic atrophy, the practicing
physician has a responsibility to become thoroughly familiar with the clinical morphology of this
condition, because it provides the most reliable early evidence of damage in glaucoma.
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Figure 4.9 Normal optic nerve heads. A: Note that size of cups is symmetric between the two eyes and
that neural rims are even for 360 degrees. C, cup; CM, cup margin; DM, disc margin; K, kinking of
vessels at cup margin; NR, neural rim; RV, retinal vessels. B: Fundus photo of a normal right eye. C,
approximation of the cup; NR, neural rim.
Morphology of the Normal Optic Nerve Head
To recognize pathologic alterations of the optic nerve head, one must first be familiar with the wide
range of normal variations.
General Features
The ophthalmoscopic appearance of the optic nerve head is generally that of a vertical oval, although
there is considerable variation in size and shape. Clinical studies have revealed a greater than sixfold
difference in the area of normal nerve heads (267, 268), which is consistent with histologic studies cited
earlier (2, 3 and 4). The central portion of the disc usually contains a depression, the cup, and an area of
pallor, which represents a partial or complete absence of axons, with exposure of the lamina cribrosa.
Although the size and location of cup and pallor are normally the same, this is not always the case,
especially in disease states (121), and these two parameters should not be thought of as being
synonymous. The tissue between the cup and disc margins is referred to as the neural rim. It represents
the location of the bulk of the axons and normally has an orange-red color because of the associated
capillaries. Retinal vessels ride up the nasal wall of the cup, often kinking at the cup margin before
crossing the neural rim to the retina (Fig. 4.9).
Physiologic Neural Rim
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By tradition, more is said about the cup than the neural rim of normal and glaucomatous optic nerve
heads. However, it is actually alterations in the neural rim of an eye with glaucoma that lead to changes
in the cup and to loss of visual field. The cup-to-disc ratio is only an indirect measure of the amount of
neural tissue in the optic nerve head and may be misleading, because a larger diameter of the nerve head
may be associated with a thinner neural rim width and larger cup size despite a stable number of axons
(269, 270). It is important, therefore, to pay close attention to the appearance of the neural rim.
The neural rim of the normal optic nerve head is typically broadest in the inferior quadrant, followed by
the superior
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and then the nasal rims, with the temporal rim being the thinnest (267). Several studies have attempted
to correlate the area of the neural rim with that of the disc, and there is general agreement that the two
are positively correlated—that is, larger discs have larger neural rim areas (267, 271, 272 and 273).
However, the contour of the cup influences this correlation, in that the relative rim area is typically
larger in discs with flat temporal sloping than in those with circular steep cups (273). The increase in
neural rim area with increasing disc area appears to be due, at least in part, to a greater number of
ganglion cell axons (4).
Figure 4.10 Gray crescents in the optic nerve head of a patient with large physiologic cups. The thin
crescent is seen just inside the scleral lip in the temporal quadrant of the right eye (A) and the
inferotemporal quadrant of the left (B).
Several factors can interfere with the interpretation of the neural rim width. A gray crescent in the optic
nerve head has been described, which typically is slate gray and located in the temporal or
inferotemporal periphery of the neural rim (274). It is more common in blacks and apparently represents
a variation of the normal anatomy. However, mistaking the gray crescent for a peripapillary pigmented
crescent could result in the physiologic neural rim's being misinterpreted as pathologically thin in that
area (Fig. 4.10).
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Figure 4.11 Oblique insertion of optic nerve heads in myopic eyes can obfuscate the interpretation of the
neuroretinal rim and creates a wide temporal peripapillary crescent. In this case, the asymmetry and loss
of the superonasal rim of the right eye corresponds to glaucomatous damage.
Another source of error in interpreting the neural rim is the optic nerve head in myopia, in which the
oblique insertion of the nerve may lead to distortion of the temporal neural rim from ophthalmoscopic
view, suggesting pathologic thinning of this tissue (Fig. 4.11). Other features of highly myopic discs that
may interfere with interpretation include a relatively large disc area; a shallower-than-usual cup, which
may mask the deepening of the cup in glaucoma; and a temporal peripapillary crescent, which may be
confused with peripapillary pigmentary changes that are seen more frequently around some
glaucomatous discs (275).
The rim area appears to decline with age and with increasing IOP (276, 277). It has also been observed
that patients with diabetes mellitus may have an increase in the neural rim over time, which could be due
to nerve swelling (278).
Physiologic Peripapillary Retina
Retinal Nerve Fiber Layer
Striations in the RNFL are normally seen ophthalmoscopically as light reflexes from bundles of nerve
fibers (62, 279) (Fig. 4.1).
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They are visible only after the bundles reach a critical thickness and are consequently seen best in the
posterior pole and peripapillary regions, especially at the vertical poles of the disc and extending
temporally from them (280). Under white light, the nerve fiber layer appears as a whitish haze over the
retina and retinal vessels. In one large study, the RNFL was most visible in the inferior temporal arcade,
followed by the superior temporal arcade, then the temporal macular area, and finally the nasal area
(281). The nerve fiber layer has been noted to decrease with age (104, 281). The visibility of the nerve
fiber layer has been shown to correlate with the width of the neural rim and the caliber of the retinal
artery (282). The relative height of the nerve fiber layer, especially when combined with visual field
mean defect, has been shown to discriminate best between glaucomatous and nonglaucomatous eyes
(283).
Peripapillary Pigmentary Variations
The normal optic nerve head may be surrounded by zones that vary in width, circumference, and
pigmentation. A clinicopathologic study has revealed several clinical configurations with anatomic
correlations (284, 285). A scleral lip, which appears commonly as a thin, even, white rim that marks the
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disc margin, usually for the full 360 degrees, represents an anterior extension of sclera between the
choroid and optic nerve head. A chorioscleral crescent, also called zone beta (Fig. 4.12), is a broader but
more irregular and incomplete area of depigmentation, which represents a retraction of retinal pigment
epithelium from the disc margin, often associated with a thinning or absence of choroid next to the disc,
with exposure of the sclera. It is commonly seen with a tilted scleral canal, as in myopia. Large zone
beta area-to-disc area ratio was found to be associated with an increased risk for glaucomatous damage
in patients with ocular hypertension (286). A peripapillary crescent of increased pigmentation has been
called zone alpha and may represent a malposition of the embryonic fold with a double layer or
irregularity of retinal pigment epithelium. It may be peripheral to zone beta or may be adjacent to the
disc if the zone beta is absent.
Figure 4.12 Zones of the optic nerve head and peripapillary pigmentation. 1. Cup. 2. Neuroretinal rim. 3.
Scleral lip. 4. Zone beta. 5. Zone alpha.
Physiologic Cup
Size
The size of the optic nerve head cup, which is commonly described as the horizontal and vertical cup-todisc ratio, varies considerably in the normal population, possibly because of normal variation in disc
diameter (4). Reports of cup-to-disc ratio distribution in the general population differ according to the
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examination technique used. When the discs were studied by direct ophthalmoscopy, the distribution
was found to be nongaussian, with most eyes having a cup-to-disc ratio of 0.0 to 0.3 and only 1% to 2%
being 0.7 or greater (287). However, when stereoscopic views were used, a gaussian distribution was
found with a mean cup-to-disc ratio of 0.4, and approximately 5% were 0.7 (288). In another study, the
two techniques of optic nerve head evaluation were compared, and stereoscopic examination with a
Hruby lens gave consistently larger cup-to-disc ratio estimates, with a mean of 0.38, compared with 0.25
by direct ophthalmoscopy (289). The investigators noted that the disparity between estimated cup-todisc ratios for the same eye at different times seldom exceeds 0.2, so that the documentation of such a
difference over time should be viewed with suspicion (289). Also of note, physiologic cups tend to be
symmetric between the two eyes of the same individual (287, 288, 289, 290 and 291), with a cup-to-disc
ratio difference of greater than 0.2 between fellow eyes occurring in only 1% to 6% of the normal
population but in 24% of patients with COAG (287, 292). However, asymmetry alone was not found
useful in identifying patients with COAG (292).
The size of the physiologic cup is frequently similar to that of the individual's parents and siblings (287,
293, 294). In other cases, the large cup may be the earliest sign of glaucoma in relatives (295). The size
of the physiologic cup is thought to be genetically determined on a polygenic, multifactorial basis (287,
296). The heritability has been estimated at two thirds, with the remaining variance attributed to
environmental factors (294). Therefore, examining other family members is helpful in distinguishing
between a large physiologic cup and glaucomatous cupping. The physiologic cup-to-disc ratio does not
appear to correlate with a family history of COAG (287, 297), although some studies have suggested a
weak correlation with higher IOP, abnormal tonographic outflow facilities, or highly positive pressure
responses to topical corticosteroid use (269, 288, 297, 298 and 299). Other studies, looking primarily at
disc area, showed significantly larger discs in patients with normal-tension glaucoma than in patients
with COAG or control participants, and suggested that large discs have increased susceptibility to
glaucomatous damage at normal pressures (300, 301). However, another study found no apparent
differences between COAG and normal-tension glaucoma in morphometric parameters measured by
scanning laser ophthalmoscopy (302).
Most studies have shown no significant correlation between age and the size of the physiologic cup (5,
267, 293, 303), whereas other investigations suggest that both the cup and pallor do enlarge slightly with
increasing age (269, 288, 289, 304, 305). Any
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enlargement of the cup with age is gradual and should not be confused with the more rapid progression
of glaucomatous cupping.
Racial differences in optic nerve head parameters have been shown, with African-Americans having a
larger disc and cupto-disc ratio than whites (303, 306, 307, 308 and 309). This racial difference has also
been demonstrated in children (310). Cup area and depth were larger in African-Americans than in
whites in one study; however, structural characteristics of the optic nerve head associated with glaucoma
were independent of differences in disc area (309).
Most studies have found no correlation between cup size and sex (287, 288, 293, 294), although one
investigation revealed larger relative areas of pallor in white male patients than in white female patients
(305), and others showed that men had slightly larger discs than women (5, 303). Refractive errors do
not appear to correlate with the diameter of the physiologic cup (267, 269, 287, 293, 303), although a
study of highly myopic eyes (>8.00 diopters [D]) revealed a significant correlation between refraction
and disc size (275).
In the differential diagnosis of glaucomatous optic atrophy, it is important to distinguish between a large
physiologic cup and glaucomatous enlargement of the cup (Fig. 4.13). One distinguishing feature is
symmetry of cup size between the right and left eyes in the physiologic state, taking into consideration
the normal variations. Another helpful feature is the configuration of the cup and neural rim and the
appearance of the peripapillary pigmentation and RNFL, which are the same in eyes with large or
normal-size physiologic cups (311). The most important feature, however, is documented progressive
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cup enlargement, which is highly suggestive of glaucoma.
Figure 4.13 A: Large physiologic optic nerve head cups that are symmetrical and intact. B:
Corresponding OCT image shows normal retinal NFL measurements.
Shape
The shape of the physiologic cup is roughly correlated with the shape of the disc, which means that the
margins of cup and disc tend to run more or less parallel (312). However, as previously noted, the
inferior neural rim is the broadest of the four quadrants, followed by the superior, nasal, and temporal
rims (267). Consequently, the cup has a horizontally oval shape in most normal eyes; thus, a vertical
cup-to-disc ratio greater than the horizontal cup-to-disc ratio should be considered suspicious (267, 289).
Morphology of Glaucomatous Optic Atrophy
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The disc changes associated with glaucoma are typically progressive and asymmetric and present in
various characteristic clinical patterns. It may be helpful to think of these in three categories: (a) disc
patterns, (b) vascular signs, and (c) peripapillary changes.
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Figure 4.14 Inferior enlargement of cup (arrow) from original cup margin (dotted line) in glaucomatous
optic atrophy, creating a polar notch (PN).
Disc Patterns of Glaucomatous Optic Atrophy
As bundles of axons are destroyed in an eye with glaucoma, the neural rim begins to thin in one of
several patterns. One study, using confocal scanning laser ophthalmoscopy, found that half of patients
with early glaucoma had smaller disc area with focal rim damage or no detectable damage, and the other
half had larger discs with diffuse rim damage (313).
Focal Atrophy
Selective loss of neural rim tissue in glaucoma occurs primarily in the inferotemporal region of the optic
nerve head and, to a somewhat lesser extent, in the superotemporal sector in the early stages of damage,
which leads to enlargement of the cup in a vertical or oblique direction (314, 315, 316, 317, 318, 319,
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320, 321, 322, 323 and 324) (Fig. 4.14). In contrast to the normal optic nerve head, the inferior temporal
rim in the glaucomatous eye is usually thinner than the superior temporal area, and the horizontal-tovertical cup-to-disc ratio is reduced (321, 322). The neural rim area is typically smaller in glaucomatous
discs than in nonglaucomatous discs, and this is a better parameter than cup-to-disc ratio in
distinguishing eyes with early glaucoma from healthy eyes (321, 325, 326). As previously noted,
however, the wide range of neural rim areas in normal eyes even limits the usefulness of this parameter.
As the glaucomatous process continues, the temporal neural rim is typically involved after the vertical
poles, with the nasal quadrant being the last to be destroyed (322).
The focal atrophy of the neural rim often begins as a small, discrete defect, usually in the inferotemporal
quadrant, which has been referred to as polar notching, focal notching, or pitlike changes (316, 317, 318
and 319). As the focal defect enlarges and deepens, it may develop a sharp nasal margin (316). When
the local thinning of neural rim tissue reaches the disc margin (i.e., no visible neural rim remains in that
area), a sharpened rim is said to be produced. If a retinal vessel crosses the sharpened rim, it will bend
sharply at the edge of the disc, creating what has been termed bayoneting at the disc edge.
Concentric atrophy
In contrast to focal atrophy, glaucomatous damage may less commonly lead to enlargement of the cup in
concentric circles, which are sometimes horizontal, but are more often directed infratemporally or
superotemporally (317). Because the loss of neural rim tissue usually begins temporally and then
progresses circumferentially toward these poles, this has been called temporal unfolding (316, 317). In
one study, this generalized expansion of the cup, with retention of its “round” appearance, was the most
common form of early glaucomatous damage (327). Because distinguishing this type of glaucomatous
cup from a physiologic cup is difficult, it is important to compare the cup in the fellow eye for symmetry
and to study serial photographs for evidence of progressive change.
A thinning of the neural rim may be seen as a crescentic shadow adjacent to the disc margin as the
intense beam of a direct ophthalmoscope passes across the neural rim (328). The histologic explanation
for this phenomenon is uncertain, but it is thought to be associated with early glaucomatous damage and
should not be confused with the previously discussed gray crescent in the optic nerve head (274, 329).
Deepening of the Cup
In some cases, the predominant pattern of early glaucomatous optic atrophy is a deepening of the cup,
which has been said to occur only when the lamina is not initially exposed (330). This may produce the
picture of overpass cupping, in which vessels initially bridge the deepened cup and later collapse into it
(316, 317). Exposure of the underlying lamina cribrosa by the deepening cup is often recognized by the
gray fenestra of the lamina, which has been referred to as the laminar dot sign (316). In most cases, the
fenestrae of the lamina cribrosa have a dotlike appearance on ophthalmoscopy, although some are more
striate and the latter configuration may have a higher association with glaucoma (331, 332).
Pallor-Cup Discrepancy
In the early stages of glaucomatous optic atrophy, enlargement of the cup may progress ahead of that of
the area of pallor. This biphasic pattern differs from other causes of optic atrophy in which the area of
pallor is typically larger than the cup (121). A potential pitfall in interpreting optic nerve head cupping is
to look only at the area of pallor and miss the larger area of cupping. The latter can usually be
recognized by observing kinking of vessels at the cup margin or by examining the disc with stereoscopic
techniques. Although the pallor-cup discrepancy is typical and strongly suggests glaucomatous cupping,
it may also be seen in some normal optic nerve heads (333).
Pallor-cup discrepancy may occur with diffuse or focal enlargement of the cup. Saucerization refers to a
pattern of early glaucomatous change in which diffuse, shallow cupping extends to the disc margins with
retention of a central pale cup (Figs. 4.15 and 4.16) and may be an early sign of glaucoma (334, 335).
Focal saucerization refers to a more localized shallow, sloping cup, usually in the inferotemporal
quadrant (317). The retention of normal neural rim color in the area of focal saucerization has been
called the tinted hollow (316). As the glaucomatous damage progresses, the color is replaced by a
grayish hue, termed the shadow sign, or by the laminar dot sign (Figs. 4.17 and 4.18).
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Figure 4.15 Glaucomatous optic atrophy. Pallor-cup discrepancy. A: Saucerization with corresponding
cross-sectional view. B: Focal saucerization with tinted hollow (TH) between pallor margin (PM) and
cup margin (CM). Note kinking of vessels in both cases.
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Figure 4.16 A: Saucerization of optic nerve head, evidenced by gradual sloping of vessels (arrowheads).
B: Topographic map using confocal scanning laser ophthalmoscopy (HRT-II) of the same optic nerve
shows the loss of neuroretinal tissue. The vessel path gives the appearance of saucerization.
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Figure 4.17 Inferotemporal loss of neural rim in glaucomatous optic atrophy, creating a sharpened rim
(SR) at the disc margin, a sharpened polar nasal edge (SPNE) along the cup margin, bayoneting at the
disc edge (BDE) where the vessels cross the sharpened rim, and laminar dot sign (LDS) due to exposure
of fenestrae in lamina cribrosa.
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Figure 4.18 A: Thinning of neural rim and “bayoneting” of a blood vessel at the site of a hemorrhage 2
years earlier. B: Corresponding visual field. Note the development of a superior paracentral scotoma.
(From Jindal A, Fudemberg S. Primary open-angle glaucoma [Chapter 52]. In: Tasman W, Jaeger EA,
eds. Duane's Clinical Ophthalmology. Vol 3. Philadelphia: Lippincott Williams & Wilkins; 2010.)
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Figure 4.19 A:: Advanced glaucomatous optic atrophy with nearly total cupping of the optic nerve head
associated with the presence of shunt vessels inferotemporally and nasally. B: Confocal scanning laser
ophthalmoscopic topography demonstrates only a small amount of nasal rim remaining.
Advanced Glaucomatous Cupping
If the progressive changes of glaucomatous optic atrophy are not arrested by appropriate measures to
reduce the IOP, the typical course is eventual loss of all neural rim tissue. The ultimate result is total
cupping, which is seen clinically as a white disc with loss of all neural rim tissue and bending of all
vessels at the margin of the disc (Fig. 4.19). This has also been called bean-pot cupping, because the
cross section of a histologic specimen reveals extreme posterior displacement of the lamina cribrosa and
undermining of the disc margin (Fig. 4.20) (317, 318).
Vascular Signs of Glaucomatous Optic Atrophy
Optic Disc Hemorrhages
Splinter hemorrhages, usually near the margin of the optic nerve head (Figs. 4.21 and 4.22), are a
common feature of glaucomatous damage (336, 337, 338 and 339). They occur more commonly
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in patients with normal-tension glaucoma than in patients with COAG or suspected glaucoma, with
cumulative incidences of 35.3%, 10.3%, and 10.4%, respectively (338). They tend to come and go, so
that they may be seen on one visit and be gone the next, only to reappear at a later date in the same or a
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new location (340). One study has shown that 95.3% of disc hemorrhages were localized on or within 2
clock hours of an RNFL defect (341). Although they typically cross the disc margin, the papillary
portion often disappears first during resorption, leaving the appearance of an extrapapillary hemorrhage
(340). The most common location is the inferior quadrant, although they may be seen superiorly or at
any other point around the disc margin. They are seen most often in the early to middle stages of
glaucomatous damage and decline in frequency with advanced damage, rarely appearing in quadrants
with absent neural rim (339); however, a thin neuroretinal rim was found to be a risk factor for the
development of optic disc hemorrhages (342). Although not pathognomonic of glaucoma, disc
hemorrhages are a significant finding, because they may be the first sign of glaucomatous damage, often
preceding RNFL defects, notches in the neural rim, and glaucomatous visual field defects (343, 344, 345
and 346). They are especially suggestive of glaucoma when associated with high IOP (347). However,
as previously noted, disc hemorrhages commonly occur with minimal pressure elevation or in eyes with
normal-tension glaucoma (338, 348). If the glaucoma patient also has diabetes, disc hemorrhages are
more common. Disc hemorrhages occur more commonly in diabetic versus nondiabetic patients with
glaucoma (349, 350). Although disc hemorrhages are not invariably associated with an increased rate of
disc damage, they are often associated with progressive changes of the visual field and should be viewed
as a sign that the glaucoma may be out of control (336, 337, 347, 350, 351, 352, 353 and 354). It has
also been noted that patients with hightension glaucoma and disc hemorrhages have a significantly
higher prevalence of neurosensorial dysacousia than those without hemorrhages do, which was thought
to suggest a common vascular denominator in both conditions (355).
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Figure 4.20 Advanced glaucomatous optic atrophy with total (bean-pot) cupping, shown best in crosssectional view.
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Figure 4.21 Vascular changes in glaucomatous optic atrophy. SH, splinter hemorrhage; BCV, baring of
circumlinear vessel.
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Figure 4.22 Splinter (“Drance”) hemorrhage in glaucomatous optic nerve. Inset shows the corresponding
automated achromatic visual field with nasal step and superior arcuate defect affecting the
papillomacular bundle.
Tortuosity of Retinal Vessels
Tortuosity of retinal vessels on the disc may be seen with advanced glaucomatous optic atrophy, and in
some cases with only moderate damage. It is believed to represent loops of collateral vessels in response
to chronic central retinal vessel occlusion (356). Venovenous anastomoses associated with chronic
branch retinal vessel occlusion, and the typical picture of acute central retinal vessel occlusion with
massive flame hemorrhages, also occur with increased frequency in eyes with chronic glaucoma (356).
Asymptomatic venous stasis changes on the disc, which are seen as enlargement of collateral vessels,
have been estimated to occur in
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3% of patients with early to moderate glaucoma, and may be associated with progression of
glaucomatous optic atrophy (357).
Cilioretinal Arteries
One study of 20 patients with bilateral symmetric COAG and unilateral cilioretinal arteries revealed a
larger cup-to-disc ratio and more visual field damage in the eye with the cilioretinal artery (358).
However, a similar study did not support this observation (359), whereas another suggested that
glaucomatous eyes with one or more temporal cilioretinal arteries were more likely to retain central
visual field than similar eyes with no cilioretinal artery (360).
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Location of Retinal Vessels The location of retinal vessels in relation to the cup may also have some
diagnostic value. The significance of overpass cupping, in which vessels bridge a cup that is becoming
deeper (316, 317), is mentioned previously. Another vessel sign with some diagnostic value has been
called baring of the circumlinear vessel (361, 362). In many normal optic nerve heads, one or two
vessels may curve to outline a portion of the physiologic cup. With glaucomatous enlargement of the
cup, these circumlinear vessels may be “bared” from the margin of the cup (Fig. 4.21). This sign may
occasionally be seen with nonglaucomatous disorders of the optic nerve and in some individuals with
physiologic cups (362, 363), although its presence in a glaucoma suspect group was associated with the
development of visual field loss (364).
It was once taught that nasal displacement of the retinal vessels on the optic nerve head was a sign of
glaucomatous cupping. However, because these vessels enter and leave the eye along the nasal margin
of the cup, their location on the disc is a function of cup size, whether physiologic or glaucomatous, and
does not provide a useful diagnostic parameter (298). On the other hand, the vertical eccentricity of the
central retinal vessel trunk (where the vessels enter and leave through the disc) may be related to the
course of glaucomatous optic atrophy (365). In one study, neural rim loss was more likely to occur in the
vertical quadrant that was further from the trunk (366).
Figure 4.23 Nerve fiber layer defect in glaucoma. A: Inferior nerve fiber layer wedge defect. B:
Corresponding superior visual field defect. (From Kwon YH, Caprioli J. Primary open-angle glaucoma
[Chapter 52]. In: Tasman W, Jaeger EA, eds. Duane's Clinical Ophthalmology. Vol 3. Philadelphia:
Lippincott Williams & Wilkins.)
Retinal vessels beyond the disc margins may also undergo changes in glaucoma. One study showed
proximal constriction (narrowing of retinal arteries near the disc) in 42% of patients with high-tension
and normal-tension glaucoma, which correlated with the sectors of greatest cupping (367). General
arterial narrowing (throughout the retinal course) was seen in 52% to 78%, corresponding to the overall
severity of optic nerve damage. However, similar findings were also seen in patients with nonarteritic
anterior ischemic optic neuropathy.
Peripapillary Changes Associated with Glaucomatous Optic Atrophy
Nerve Fiber Bundle Defects
The loss of axonal bundles, which leads to the neural rim changes of glaucomatous optic atrophy, also
produces visible defects in the RNFL. These appear as dark stripes or wedge-shaped defects of varying
width in the peripapillary area, paralleling the normal retinal striations, or as diffuse loss of the striations
(368, 369, 370 and 371) (Fig. 4.23). They often follow disc hemorrhages and correlate highly with
visual field changes, neural rim area, and fluorescein-filling defects (343, 368, 369, 370, 371, 372, 373
and 374). RNFL defects are also seen in many neurologic disorders, as well as in patients with ocular
hypertension and healthy individuals. However, attention to the appearance of the defects in glaucoma
has improved the sensitivity and specificity of this finding, and several studies have shown RNFL
defects to be the most useful parameter in the early detection of glaucomatous damage (375, 376, 377
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and 378). The diffuse loss is more common in patients with glaucoma than in patients with ocular
hypertension (379), but it is also more common among persons with ocular hypertension than among
those with normal IOPs (380). Localized defects
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are more directly associated with localized visual field loss than is the case with diffuse nerve loss (381).
Either localized or diffuse loss may be the initial sign of glaucomatous damage (382).
Peripapillary Pigmentary Disturbance
Peripapillary pigmentary disturbance is frequently associated with glaucomatous optic atrophy, but is
also seen with other conditions, such as myopia and aging changes. As previously noted, several
variations of peripapillary pigmentary change may be seen in healthy eyes. The scleral lip, or
peripapillary halo, is a narrow, homogenous light band at the edge of the disc. The incidence of
prominent halos is higher in glaucoma, although the average degree of halos is statistically the same as
in nonglaucomatous eyes (383). Peripapillary atrophy (both zone beta and zone alpha, as previously
described) occurs more frequently and is larger in eyes with glaucomatous damage than in normal eyes,
and it has been observed to progressively enlarge in eyes with glaucoma (384, 385, 386 and 387). It
increases with decreasing neural rim area and correlates with the quadrants of the greatest rim loss
(388). There is evidence that the absence of peripapillary atrophy may be associated with a decreased
risk of glaucomatous damage among patients with ocular hypertension (389, 390).
Reversal of Glaucomatous Cupping
It is generally taught that glaucomatous damage of the optic nerve head and visual field is an irreversible
process. Although this may be true in many cases, especially when associated with actual loss of axons,
there are situations in which glaucomatous damage may be at least partially reversible. Because of
increased elasticity of their sclera, this is most commonly observed in children with early stages of
glaucoma, particularly during the first year of life, when the IOP is successfully lowered surgically (391,
392). However, improvement in the cup, neural rim, and even the nerve fiber layer height have been
described in adults after a marked reduction in IOP by surgical or medical means (393, 394, 395, 396,
397, 398 and 399). It is important to point out that “reversal of cupping” represents a mechanical effect
of IOP reduction and not an increase in neuroretinal tissue.
Figure 4.24 Colobomas of the optic nerve heads can simulate glaucomatous cupping. This patient would
appear to have nearly total cupping and pallor, and yet the IOP was low normal and the visual fields
were full with normal central vision.
DIFFERENTIAL DIAGNOSIS OF GLAUCOMATOUS OPTIC ATROPHY
Normal Variations
Normal variations in the physiologic cup, the neural rim, and the peripapillary retina, as discussed earlier
in this chapter, may be confused with the changes of glaucoma. In addition, developmental anomalies
and nonglaucomatous optic atrophies may be sources of diagnostic confusion.
Developmental Anomalies
Colobomas of the optic nerve head can simulate glaucomatous cupping. The defect may involve the
entire disc, which is enlarged and excavated (400, 401) (Fig. 4.24). In some cases, the diagnostic
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problem is compounded by associated field defects, which may resemble those of glaucoma, but are
typically not progressive. A variation of optic nerve head colobomas, called the morning glory
syndrome, is characterized by a large funnelshaped staphylomatous coloboma of the nerve head and
peripapillary region with white central tissue, elevated peripapillary pigment disturbance, and multiple
radially oriented retinal vessels (402, 403 and 404). Morning glory syndrome is typically seen only in
one eye and is usually not inherited; however, bilateral cases, which may be hereditary, have been
reported (405, 406).
Another optic nerve head anomaly that may represent an atypical coloboma is the congenital pit (403,
404). This is a localized, pale depression, usually near the temporal or inferotemporal margin of the disc,
although it may be found in any area of the nerve head, and there may be two, or even three, pits in
some eyes. These anomalies may have associated visual disturbance resulting from macular or
extramacular serous detachment (407), in which the optic disc pit may act as a conduit for fluid flow
from the schisis cavity into the subarachnoid space (408). The serous detachment may resolve
spontaneously (409). Cases have also been reported in which congenital pits were noted to enlarge when
observed for many years (410).
Tilted disc syndrome is a congenital anomaly in which the optic disc is tilted on its horizontal axis, with
inferior chorioretinal hypoplasia (411). Although tilted disc syndrome is less
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likely than the colobomas to be confused with glaucoma, it can interfere with the recognition of
glaucomatous damage, which is compounded by superotemporal visual field loss.
Nonglaucomatous Optic Nerve Atrophy
Ophthalmologists cannot always distinguish between glaucomatous and nonglaucomatous optic atrophy
on the basis of the optic disc appearance alone (412). Parameters that are most useful in making this
differentiation include pallor of the neural rim in nonglaucomatous eyes and obliteration of the rim in
glaucoma (413). Nonglaucomatous conditions that may cause acquired cupping include anterior
ischemic optic neuropathy (as previously discussed), especially when the ischemia is due to arteritis
(256, 257 and 258). A similar entity has been described in which infarction of the optic nerve head
caused shallow cupping infratemporally, associated with arcuate field defects (414). This differed from
glaucoma in that it was not progressive. Acquired cupping may also occur with compressive lesions of
the optic nerve, such as an intracranial aneurysm, which was reported to cause cupping indistinguishable
from that of early glaucoma (415). Nonglaucomatous optic neuropathies are also associated with loss of
the RNFL, but with minimal cupping (416).
EVALUATION TECHNIQUES
Progressive cupping of the optic nerve head in a patient with glaucoma is the most reliable indicator that
the IOP is not being adequately controlled. It is essential, therefore, to evaluate and record the
appearance of the nerve head in a way that will accurately reveal subtle glaucomatous changes over the
course of follow-up evaluations. In current practice, this involves careful evaluation in the office
combined with photographic documentation. In addition, newer automated techniques may provide
more precise methods of observation.
Office Evaluation and Recording of the Optic Nerve
In the clinical evaluation of the optic nerve head, the direct ophthalmoscope is occasionally useful,
especially when evaluating the nerve fiber layer with a red-free filter. However, this technique does not
permit detection of many of the glaucomatous changes in the nerve head and peripapillary area, and the
most useful office approach is to carefully study these structures with stereoscopic methods. The most
useful stereoscopic technique involves use of a slitlamp and an auxiliary fundus lens, such as the
Goldmann contact lens, the handheld 78-D lens or 90-D lens (Fig. 4.25), or the Hruby lens slitlamp
attachment. Each of these systems provides the advantages of magnification and stereopsis. However,
because the lateral and axial magnifications are unequal, there is a certain amount of image distortion,
with the Goldmann and handheld lenses producing a decrease in apparent depth and the Hruby lens
producing a slight increase (417).
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Several methods have been described for estimating the size of the disc and neural rim. These include
use of (a) a direct ophthalmoscope, using either the graticule incorporated in the instrument or the
smallest round white light spot of the Welch Allyn direct ophthalmoscope, which projects a 1.5-mm
diameter spot on the retina in most eyes (418, 419); (b) an indirect ophthalmoscope with a spacing
device on the condensing lens that allows measurement of the disc image with calipers (420, 421); and
(c) a Haag-Streit slitlamp with a 90-D lens or contact lens (422, 423 and 424), in which the height of the
slit beam is adjusted to coincide with the disc edges and is then read off the scale. When compared with
more quantitative measurements, such as planimetry, these techniques provide reasonably accurate
estimates, especially when appropriate correction factors are considered.
Figure 4.25 A 90-D lens used with slitlamp for stereoscopic indirect ophthalmoscopic evaluation of
optic nerve head.
Subjective estimates of cup dimensions vary greatly, even among expert observers (425, 426, 427 and
428). These can be improved by paying attention to the many complex optic nerve head and
peripapillary retinal parameters associated with glaucomatous damage and to the need for standardized
methods for interobserver evaluation of the optic disc (427, 429, 430). Detailed drawings should include
the area of cupping and pallor in all quadrants, the position and kinking of major vessels, splinter
hemorrhages, and peripapillary changes. However, no degree of attention to detail is sufficient to detect
subtle changes in all cases, and the office evaluation should be considered only as an adjunct to the
indispensable use of photographic records or other imaging records.
Photographic Techniques
Two-Dimensional Photographs
Two-dimensional photographs, whether color or black-andwhite, have the advantages of simplicity and
lower cost, compared with stereophotographs and computed images. In addition, the relative dimensions
of the pallor and cup can be measured directly on the photograph (431, 432). Although one study found
monocular and stereoscopic photographs to afford similar levels of accuracy (433), the former technique
is frequently limited by the inability to precisely determine the cup margins. The projection of fine
parallel lines onto the disc has been suggested as a way to improve recognition of the cup contours on
two-dimensional photographs
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and stereophotographs (434, 435). Techniques have also been developed to electronically scan blackand-white disc photos to obtain an objective measure of the amount of optic disc pallor (436, 437). The
main value of two-dimensional photos in the future may be to document the RNFL. Special techniques
to enhance the subtle details of this parameter include monochromatic (red-free) filters and highresolution film, crosspolarization photography, a wide-angle fundus camera, a spectral reflectance, and a
charge-coupled device with digital filtering (438, 439, 440, 441, 442, 443, 444, 445 and 446). The use of
nerve fiber layer photography compared favorably with other glaucoma-screening methods in a general
medical clinic setting (442).
Stereoscopic Photographs
A more reliable method for recording disc cupping and the other aspects of glaucomatous optic atrophy
is the use of color stereophotographs. Stereophotographs can be obtained by taking two photos in
sequence, either by manually repositioning the camera or by using a sliding carriage adapter (Allen
separator), or by taking simultaneous photos with two cameras that utilize the indirect ophthalmoscopic
principle (Donaldson stereoscopic fundus camera) or a twin-prism separator (447, 448, 449 and 450).
These three techniques were compared for reproducibility, and the Donaldson camera was found to be
superior (451). However, use of a simultaneous stereo camera, which provides the stereo pair on two
halves of the same frame (Nidek 3Dx), had significantly better overall mean stereoscopic quality than
the Donaldson camera (452). Transparencies from the Nidek camera can also be used to create lenticular
images, which are single prints on a unique, photosensitized plastic base that produces a threedimensional image without use of a stereoviewer (453). Although simultaneous stereophotography may
be optimal for assessing the optic nerve head, no manufacturers currently make these cameras.
Ultrasonography
Ultrasound can be used to detect glaucomatous cupping of 0.7 cup-to-disc ratio or greater (454).
Computed Analysis of the Optic Nerve Head and RNFL
Historical Perspective
Even the most sophisticated fundus photographs are limited in their clinical value by the qualitative,
subjective interpretation of the images (426). Efforts to refine the assessment of these subtle findings
have included quantitative analyses of optic nerve head topography and pallor, and RNFL height or
thickness. These techniques were initially performed manually (455), which was time consuming and
impractical for routine clinical practice. With the advent of computers and newer imaging technologies,
however, applying these concepts to the clinical management of glaucoma is now a possibility.
The concept of computed image analysis of the optic nerve head was pioneered by Dr. Bernard
Schwartz, who developed prototypes for analysis of contour and pallor of the disc (456).
Early instruments used the basic principle of stereopsis, in which disparity between corresponding points
of stereo pair images was used to generate contour lines and three-dimensional contour maps
(stereophotogrammetry). Commercial instruments in this category were the Rodenstock optic nerve head
analyzer (457, 458 and 459), the Topcon Imagenet (460), and the Humphrey retinal analyzer (461). The
Topcon Imagenet and Humphrey retinal analyzer measured disparity between existing structures in the
stereo images, whereas the optic nerve head analyzer used projected light stripes on the disc to measure
image disparity. Stereochronoscopy used the stereoscopic principle to detect subtle changes in
photographs of a disc taken at different times (462, 463 and 464). If any progression of the cupping has
occurred, the disparity in the cup margins of the superimposed photographs would produce a
stereoscopic effect. A modification of this concept, referred to as stereo chronometry, used a
stereoplotter to measure the changes created by the two photographs (465). Other modifications for
detecting differences in serial fundus photographs involve analysis of flicker while alternately viewing
one photograph and then the other, and electronic subtraction, in which areas of disparity between the
two images are enhanced (464, 466, 467).
Colorimetric measurements have also been studied to detect reduced or changing color intensity of the
optic nerve head (468, 469, 470 and 471). A photographic technique has also been developed to permit
quantitative evaluation of the relative brightness of the illuminated optic nerve head (472).
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In another technology, rasterstereography, a series of horizontal dark-light line pairs are projected on the
disc and peripapillary retina at a fixed angle and the computer scans a video image of the lines in a raster
fashion. Raster refers to a scanning pattern that moves from side to side and from top to bottom (the
same scanning pattern used in confocal laser scanning). Because the lines are deflected proportional to
the height or depth of the disc and retinal surfaces, a computer algorithm can translate the deflections
into depth numbers and create a topographic map.
An image analyzer that used the rasterstereography concept was the Glaucoma-Scope, which is no
longer available (473, 474). It projected a near infrared light in parallel stripes on the nerve head. The
computer analyzed the data points to generate depth measures, which were displayed in microns relative
to reference planes. In the initial set of measurements, the actual depth measures were provided, while
follow-up studies showed only change of more than 50 µm from baseline.
Despite reasonable reproducibility and accuracy, these instruments never achieved widespread clinical
use primarily because of technical complexity, the size and cost of the instrument, and the need for
relatively wide pupillary dilatation and clear media. Nevertheless, the experience gained through the
study of these instruments provided the basis for much of our understanding of computed image analysis
of the optic nerve head and of the potential for clinical application of newer instruments and techniques
in the management of glaucoma.
Over the past decade, several commercially available instruments have been described. These
instruments use newer techniques, such as confocal laser scanning ophthalmoscopy and
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polarimetry, optical coherence tomography (OCT), and the retinal thickness analyzer. Imaging and
computed data processing allow for precise three-dimensional in vivo measurements. However,
computed results should always be evaluated in a clinical context (475).
Measure of Clinical Utility
For a structural test to be diagnostically useful, it should be able to (a) differentiate between healthy and
glaucomatous eyes, (b) detect glaucomatous changes earlier than functional changes (i.e., preperimetric
glaucoma—when psychophysical testing does not show an abnormality), and (c) detect progression of
disease.
Optic Nerve Topography
Principles of Confocal Scanning Laser Tomography
Confocal scanning laser ophthalmoscopy is a technique for obtaining high-resolution images by using a
focused laser beam to scan over the area of the fundus to be imaged. Only a small spot on the fundus is
illuminated at any instant, and the light reflected determines the brightness of the corresponding pixel on
a computer monitor. To improve contrast, a pinhole, or confocal aperture, is placed in front of the
photodetector to eliminate scattered light (Fig. 4.26). The aperture is conjugate to the laser focus, and the
resulting image is said to be confocal. The instantaneous volume of tissue from which reflected light is
accepted by the confocal aperture is called a voxel, and the smaller the aperture, the smaller the voxel
and the higher the resolution of the image. By scanning the fundus with the laser in a raster pattern, a
two-dimensional image can be built up as an array of pixels. If a series of confocal scanning laser
ophthalmoscopy images are obtained at successive planes of depth in the tissue, these can be used to
construct a three-dimensional image, or confocal scanning laser tomography.
The prototype in this category of instruments was the laser tomographic scanner (476, 477). Although
the laser tomographic scanner is no longer commercially available, new-generation units were
developed from the original laser tomographic scanner and are similar in basic design.
The HRT-II and HRT-III (Fig. 4.27) are completely automatic instruments designed to be used in
routine clinical practice for study of optic nerve head morphology. They are based on the original HRT,
which has had the most extensively re ported evaluation and was found to have reproducibility of
stereometric parameters comparable with the original HRT (478). The HRT-II uses a 675-nm diode laser
as a light source to measure the reflectivity of millions of points in multiple consecutive focal planes in
0.024 second per plane. The first section image is located above the reflection of the first retinal vessel,
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and the last is beyond the bottom of the optic nerve head cup, with 16 confocal images acquired per 1
mm of the scan depth, achieving high spatial resolution. The computer then converts the acquired data to
a single topographic image with 384 ×384 data points (pixels) within a 15-degree area. The calculated
image is then used to produce quantitative measurements of morphometric parameters of the disc that
can be used to classify the nerve as normal or glaucomatous, or to compare topography images to
quantify progression of glaucoma.
Figure 4.26 Principles of confocal scanning laser ophthalmoscopy.
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Figure 4.27 HRT-III. (Courtesy of Heidelberg Engineering.)
For the HRT to calculate these parameters, several preliminary steps are performed. First, a reference
ring with an outer diameter of 94% and a width of 3% of the acquired image is placed on the image to
define the retinal surface. The absolute height of that surface is then calculated, relative to the focal
plane of the eye, and the mean height of that retinal reference ring is used to calculate the relative
coordinate system, or reference plane. A correction for tilt is also made. Another surface, called the
curved surface, is then defined after a contour line is drawn around the border of the optic disc.
Topographic measurements are then calculated.
Because the magnitude of morphometric parameter values depends strongly on the chosen reference
plane (479), defining the plane becomes a critical issue. Theoretical and practical problems have
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complicated the choice of the reference plane. Various modifications of the position of the reference
plane have been offered to compensate for possible thinning of the retina during the course of glaucoma
(480, 481). The HRT software automatically defines a reference plane parallel to the peripapillary retinal
surface and 50 µm posterior to the retinal surface at the papillomacular bundle (479, 482). The rationale
for this definition is that, during development of glaucoma, the
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nerve fibers at the papillomacular bundle remain intact longest, and the nerve fiber layer thickness at
that location is approximately 50 µm. All structures located below the reference plane are considered to
be the cup, and all structures located above the reference plane and within the contour line are
considered to be the rim (Fig. 4.28). The cup of the optic nerve head is displayed in red, and the rim is
displayed in blue and green. The distance between the reference plane and the retinal surface is used to
measure the mean RNFL thickness.
Figure 4.28 A: Color photograph of a right optic nerve. B: Corresponding image from an HRT-II. The
reference planes are the red lines.
Evaluation of Accuracy and Reproducibility of Confocal Scanning Laser Tomography
Numerous reproducibility studies have been reported for the HRT (483, 484, 485, 486, 487 and 488),
revealing acceptably low variability. Tests that are reproducible will have a higher chance of detecting
progression over time. Highly reproducible topographic data can be obtained with a nondilated pupil
(485), although the accuracy and reproducibility declined when the pupil was very small or very dilated
(489). It has been suggested that reproducibility can be improved in general by using a series of three
examinations (483).
An accuracy study performed with the laser tomographic scanner by using a plastic model eye revealed
low-average relative errors for diameter and depth (477). However, vertical disc diameter measurements
with the HRT were significantly smaller than those obtained with planimetric methods (490). The
reproducibility of the stereometric parameters was evaluated in different clinical studies in normal and
glaucomatous eyes, and measurements were found to be highly reproducible (491), with typical
coefficients of variation for area, volume, and depth measurements of about 5% (486, 487).
One lesson learned from the study of image analysis of the optic nerve head is that traditional
parameters, such as cup-todisc ratio and neural rim area, are inadequate for interpreting the subtle
findings in the disc and peripapillary retina in healthy and diseased states. To address this problem, the
HRT provides a wide range of two-dimensional and three-dimensional information on the disc and
peripapillary retina, which is displayed on a monitor and in hard copy. One of these parameters is
referred to as cup shape measure, previously known as the third moment. This parameter relates to the
frequency distribution of depth values relative to the curved surfaces inside the disc area and is a
function of the overall shape of the optic nerve head. It was found to be the most useful indicator of the
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degree of glaucomatous optic nerve damage and early glaucomatous visual field loss (492, 493). In one
study, the cup shape measure was the only parameter associated with changes in visual field (494).
Other useful morphometric parameters include rim area, variation of height of contour line, and RNFL
thickness (495). Less useful parameters include disc area, cup area, cup and rim volume, and mean and
maximum cup depth. Optic nerve head parameters obtained by the HRT may be affected by age,
refraction, or disc area (494, 496). Rim volume appears to be the only parameter unaffected by these
factors (496).
The sensitivity and specificity of the various HRT topographic parameters vary significantly. In general,
the sensitivities have been reported in the low-80s to -90s (%), with specificity ranging from the low-80s
to the mid-90s (%) (497, 498, 499, 500, 501, 502 and 503). Except in eyes with advanced glaucomatous
damage, classifying an individual eye as normal or glaucomatous is difficult to do with absolute
certainty on the basis of single HRT parameters.
For better discrimination between normal and abnormal optic discs, the HRT software performs
statistical analyses to allow a comparison between the examined optic disc and a database of normal
eyes. Multivariate analysis methods that use combinations of individual parameters to classify an
individual eye into a “normal” or a “glaucoma” group have been proposed (493, 495, 504, 505, 506 and
507). These studies have shown that, when the cup shape measure, rim volume, and retinal surface
height variation are analyzed together, they appear to be the most important parameters to differentiate
between normal and glaucomatous optic nerve heads. HRT-II was also
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reported to be able to classify the optic nerve head appearance as “normal,” “borderline,” or “outside
normal limits” on the basis of the ratio of rim area to disc area (Moorfields regression analysis) (508).
However, in a prospective study, multivariate analysis and Moorfields regression analysis did not
discriminate as well between patients with glaucoma and control participants (509).
Another method to detect glaucomatous change is the ranked-segment distribution curve analysis (510).
To perform this analysis, the optic nerve head is divided into 36 sectors, each 10 degrees wide. The
stereometric parameters are then calculated for each segment, sorted in descending order, and displayed
as a graphic representation of the optic nerve head configuration. From a population of normal eyes,
rankedsegment distribution curves for the 5th and 95th percentiles are calculated, and a patient's rankedsegment distribution curve is plotted against the normal curves.
In the Ocular Hypertension Treatment Study (OHTS) and the Early Manifest Glaucoma Trial (EMGT),
conversion from ocular hypertension to glaucoma was by optic nerve criterion in 40% to 50% of cases
(511, 512). In an ancillary study of OHTS involving use of confocal scanning laser ophthalmoscopy,
large cup-disc area, mean cup depth, mean height contour, and cup volume had a positive predictive
value between 14% and 40% for the development of COAG from ocular hypertension (513).
Progression in glaucoma may be detected by calculating a change probability map (514), which uses
three images acquired during the baseline and three images during the follow-up examination. The six
images are aligned and normalized to each other. Each image cluster of 4 by 4 adjacent height
measurements or pixels is then combined to create so-called superpixels, with 48 baseline height
measurements and 48 follow-up height measurements. Then the variability of the baseline
measurements is compared with the combined variability of the baseline and follow-up measurements at
each superpixel. The resulting probability maps are displayed in color codes. White superpixels indicate
no significant change; dark-brown superpixels indicate that the surface height has changed significantly,
with an error probability of less than 5% (514).
As mentioned previously, HRT can distinguish discs with specific appearances that include focal
ischemia, myopic glaucomatous changes, senile sclerotic changes, and generalized cup enlargement by
comparing mean values for certain optic disc variables (515). However, the ability to detect
glaucomatous damage varies considerably with the disc appearance. In studies of patients with ocular
hypertension and patients with glaucoma, the HRT and visual field tests had fair to poor agreement in
detecting glaucoma (516). Therefore, in the clinical setting, caution should be used when interpreting
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HRT results on the basis of multivariate discriminant analysis or ranked-segment distribution curves.
Clinical optic disc evaluation remains the most important method of detecting or following up patients
with glaucoma, although information obtained with the HRT may have adjunctive value, and further
refinement of the instrument may increase its value.
Other confocal laser scanners, including the Rodenstock 101 confocal scanning laser ophthalmoscope,
are no longer commercially available. OCT can also be used to generate a topographic map. At the time
of publication, the absence of a normative database for comparison limits the clinical utility of OCT for
optic nerve topography.
Retinal Nerve Fiber Layer Imaging
Confocal Scanning Laser Polarimetry
A confocal scanning laser polarimeter combines the concept of a confocal scanning laser and
polarimetry to measure the RNFL thickness (517). Based on the assumption that the RNFL is
birefringent, caused by the parallel microtubules in the nerve fibers (518, 519), a polarized diode laser
light (780 nm) is changed when it penetrates the tissue. This change in the state of polarization is
referred to as retardation and is linearly related to the thickness of the RNFL (518). The computer
provides thickness data for concentric circles around the disc margin. The initial versions of this
instrument—the Nerve Fiber Analyzer (NFA)-I and NFA-II—have since been upgraded several times.
The current version, known as GDxPRO (Fig. 4.29), allows comparison of an individual's data against a
large normative database.
In one study, the location of the peak retardation values was found to be in agreement with the values of
RNFL thickness published for humans, but the retardation values around the disc were different from the
anatomic data. The authors concluded that discrepancies between the retardation and anatomic data
should be recognized in the clinical interpretation of polarimetric data (520). Differences of the corneal
polarization axis naturally exist in healthy and glaucomatous eyes; therefore, influence of corneal
birefringence should be properly compensated (521, 522). The variable corneal compensator
individually corrects for polarization induced by the cornea and the lens (523, 524, 525, 526 and 527),
improving the ability of GDx to discriminate between glaucomatous and healthy eyes. In general, the
reported sensitivity and specificity of scanning laser polarimetry to detect glaucoma are above 80%
(503, 528, 529).
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Figure 4.29 GDxPRO, a portable scanning laser polarimeter. (Courtesy of Carl Zeiss Meditec, Inc.)
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Figure 4.30 Stratus OCT. (Courtesy of Carl Zeiss Meditec, Inc.)
Optical Coherence Tomography
OCT was developed in the early 1990s and became available to ophthalmologists in 1996. A secondgeneration instrument was introduced in 2000, and a third-generation instrument, the Stratus OCT (Fig.
4.30), was introduced in 2002, achieving an increase in imaging speed and resolution. Later in the
decade, several spectral-domain OCT machines (Fig. 4.31) became widely available. The first three
generations of OCT are referred to as time-domain OCT.
The principle of OCT involves a low-coherence infrared (843-nm) diode light source, which is divided
into reference and sample paths. Reflected sample light from the patient's eye creates an interference
signal with the reference beam, which is detected in a fiber-optic interferometer. Cross-sectional images
of the retina and disc are then constructed from a sequence of signals, similar to that of an ultrasound Bmode (530). Instead of sound waves, however, the OCT uses low-coherence light to quantify RNFL
thickness, by measuring the difference in delay of backscattered light from the RNFL inside the imaged
tissue. RNFL can be differentiated from other retinal layers with an algorithm that detects the anterior
edge of retinal pigment epithelium and determines the photoreceptor layer position. Each resulting
image consists of RNFL thickness measurements along a 360-degree circle around the optic disc (531).
Multiple studies have demonstrated that RNFL thickness can be accurately measured with the OCT
(532, 533, 534, 535, 536 and 537), however it was suggested that earlier versions of the OCT may have
underestimated RNFL thickness (538). One study compared RNFL thickness measurements using the
first generations of OCT, NFA, and HRT and achieved the most reliable results with the NFA, followed
by HRT (539). However, other studies showed that the third generation of OCT was similar to scanning
laser polarimetry and HRT in differentiating glaucomatous eyes from healthy eyes (540, 541). Unlike
confocal scanning laser tomography, the OCT does not require a reference plane. Results of RNFL
thickness measurements may vary with different instruments.
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Figure 4.31 Two examples of spectral-domain OCT machines. A: Cirrus HD-OCT. (Courtesy of Carl
Zeiss Meditec, Inc.) B: Spectralis OCT. (Courtesy of Heidelberg Engineering.)
The final resolution of OCT is determined by transverse and axial resolution; transverse resolution is
determined by the spacing of the A-scan and is ultimately limited by the optics of ocular tissue. Axial
resolution varies by wavelength and bandwidth of the light source. Current models of time-domain and
spectral-domain OCT use the same diode light sources. Some ultrahigh-resolution ophthalmic OCT
scanners are based on a commercially available titanium-sapphire laser. This system enables in vivo
cross-sectional retinal imaging with axial resolution of approximately 1 to 3 µm, compared with
approximately 10 µm for the OCT3 (542, 543). These OCT devices that use the titanium-sapphire laser
sources are not commercially available because of prohibitive costs of the laser. Spectral-domain OCT
does not rely on a beam splitter or moving reference mirror; instead, all of the reflected light returns to a
spectrometer, and the wavelengths are converted by Fourier transformation to generate the images. This
allows higher resolution than a timedomain OCT does, and faster acquisition time. Theoretically, the
faster acquisition time should reduce the induced artifact from patients' eye movement, compared with
OCT3.
OCT3 has a normative database and can differentiate glaucomatous and nonglaucomatous eyes with
reported sensitivities and specificities generally ranging from the upper-60s to mid-80s (%) and the low80s to -90s (%), respectively (497, 498, 499 and 500). Thin OCT measurements are associated with the
conversion of suspected glaucoma to glaucoma (544). The utility of OCT3 for determining progression
in
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advance of functional testing is less clear. At the time of publication, comparison of spectral-domain
OCT to OCT3 with regard to diagnosing glaucoma and progression of glaucoma has not yet been
established.
Retinal Thickness Analyzer
The retinal thickness analyzer is another computerized system for measuring the retina thickness. It
projects a laser beam onto the retina, and a fundus camera observes reflections from internal limiting
membrane and in the retina until the light reaches the retinal pigment epithelium. The profile of light
intensity contains peak reflections from the internal limiting membrane and the retinal pigment
epithelium, and the thickness of the retina is calculated from the distance between the two peaks. The
retinal thickness analyzer may be useful in glaucoma management to monitor retinal thickness (545,
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546).
Clinical Value of Image Analyzers
In the few studies that have directly compared the different structural imaging technologies, OCT3 had
better sensitivity and specificity, compared with the HRT-II and scanning laser polarimetry (528, 529).
Early in the course of the disease process, these structural imaging technologies are very helpful in
differentiating glaucomatous damage before achromatic (i.e., white-on-white) visual field change.
Perhaps the most useful application is a negative result on a structural test in a patient with suspected
glaucoma; it can be reassuring that no disease is detectable when visual field and structural testing find
no abnormality. No single test has absolute sensitivity and specificity. When used alone, HRT, GDx, and
OCT summary data reports may help differentiate between healthy eyes and glaucomatous eyes with
mild to moderate visual field loss, although none of the instruments provided enough sensitivity and
specificity to be used as a screening tool for early glaucoma (547). A combination of the best parameters
from the three imaging methods significantly improves this capability (541) (Fig. 4.32). Information
obtained with HRT, GDx, and OCT allows combining qualitative data with graphic visual information
and quantitative data, and, with improved sensitivity and specificity of these instruments, the summary
data reports may better assist the physician in the management of patients with glaucoma (531).
At this time, none of these structural technologies alone can be relied on to ascertain glaucomatous
progression without corroborating evidence. However, these technologies continue to evolve and
improve rapidly. At the time of publication, HRTIII and spectral domain are at the beginning of their
use.
Techniques for Blood-Flow Measurement
Early studies on ocular blood flow are discussed earlier; they relate to the pathophysiology of
glaucomatous optic neuropathy. This section considers new techniques for measuring ocular blood flow,
which may one day have clinical application. Although studies have shown deficient blood flow in at
least 50% of patients with normal-tension glaucoma, direct evidence that vascular factors contribute to
the development of glaucoma optic neuropathy is lacking, because measurements of the optic nerve
blood flow are limited by the small caliber of blood vessels and the volume of the optic nerve tissue
being studied (548, 549 and 550).
In the past two decades, several methods have been developed to facilitate quantitative, comprehensive
study of retinal, choroidal, and retrobulbar circulations. These techniques include vessel caliber
assessment, pulsatile ocular blood-flow measurement, scanning laser fluorescein and indocyanine green
(ICG) angiography of the peripapillary choroid and the retinal circulation, laser Doppler flowmetry,
confocal scanning laser Doppler flowmetry, and color Doppler imaging (551). To fully assess optic
nerve circulation, these techniques should be combined because no single technology can adequately
describe the complex hemodynamics of the eye.
Angiography
New imaging technologies allow us to detect and follow very subtle changes of the structure and
perfusion of the optic nerve head. These and other technologies may enhance the ability to diagnose and
monitor glaucomatous disc damage (552).
Confocal scanning laser ophthalmoscopy can enhance angiographic examination of small vessels of the
optic nerve head using fluorescein or ICG (553). The confocal scanning laser ophthalmoscopy allows
acquisition of images of the retinal circulation and late leakage sites. Optical subtraction of the light
contribution of the retinal circulation allows examination of the choroidal circulation and vice versa. At
least three advantages of confocal scanning laser ophthalmoscopy over conventional instruments have
been described as follows: (a) excellent visualization of the retinal circulation, (b) optical subtraction of
retinal circulation, and (c) acquisition and processing of all data digitally with easy data exchange. This
technology may potentially produce a three-dimensional map of the retinal and choroidal vasculature
(554).
Heidelberg retina angiograph (HRA and HRA-II), which combines confocal scanning laser
ophthalmoscopy technology with ICG and fluorescein angiography, is commercially available. With this
instrument, several changes may be seen in peripapillary capillary vessels at the different glaucomatous
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stages. Persons with early glaucomatous damage have an increase of the cup area, secondary to a
reduction of the neuroretinal rim area, and ICG angiography shows an increase in prepapillary plexus
visualization, which may be caused by increased blood flow while autoregulation is still functioning.
Some patients with advanced glaucoma show significant capillary dropout on ICG angiography (555).
The HRA can demonstrate the superficial and deep blood supply of the optic nerve, and simultaneous
ICG and fluorescein angiography, and visualization of separate circulations in different planes. The
technique allows overlaying ICG and fluorescein images or comparison of them side by side (556). One
prospective study evaluated the correlation between the vascular supply of the optic nerve and visual
fields. In eyes with a normal visual field, a diffuse microvascular filling pattern of the optic disc area
was apparent with no filling defects, whereas angiography of glaucomatous eyes had good correlation
with the visual field defect location (557).
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Figure 4.32 A:Color photograph of a glaucomatous optic nerve head showing advanced loss of the
neuroretinal rim, especially inferotemporally. Peripapillary atrophy, arteriolar narrowing, and
bayoneting of the retinal arterioles are also present. B: Corresponding OCT shows preservation of the
nasal RNFL, but significant loss temporally. C: Topographic map by confocal scanning laser
ophthalmoscopy of the same optic nerve. The red x denotes areas of neuroretinal rim thickness less than
the normative database; the yellow! denotes areas of neuroretinal rim thickness in the border zone of
normal in the same normative database. D: Corresponding automated achromatic visual field showing a
near superior altitudinal defect and dense inferior arcuate and nasal step defect. E: Cross section of the
optic nerve head by OCT. F: Topographic map by OCT of the same optic nerve.
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When the optic disc and peripapillary region was evaluated by modified ICG confocal scanning laser
ophthalmoscopy angiography, the hypofluorescent areas in the peripapillary region were more common
in eyes with glaucoma; however, hypofluorescent halos that were extending around the optic disc
margins did not correlate with any of the study factors. Hypofluorescence was demonstrated in 68% of
glaucomatous eyes, compared with 20% of control eyes (558). These observations are similar to those of
earlier fluorescein angiographic studies that were previously discussed.
Color Doppler Imaging
The normal vascular anatomy of the eye and orbit, and various conditions with vascular abnormalities,
has been studied with the color Doppler imaging, which allows simultaneous imaging with real-time
ultrasound and superimposed color-coded vascular flow, allowing visualization of vessels previously
beyond the resolution of conventional imaging, such as those in the orbit (559). Combining B-scan
ultrasonography and Doppler waveform analysis, color Doppler imaging has been reported to allow
noninvasive examination of blood velocity and vascular resistance in the ophthalmic, short posterior
ciliary, and central retinal arteries in patients with COAG or normal-tension glaucoma (167).
One investigative team, using color Doppler imaging to evaluate the blood flow in the ophthalmic,
posterior ciliary, and central retinal arteries, found significantly reduced mean systolic peak flow
velocity in the ophthalmic artery in patients with glaucoma, compared with controls. In patients with
glaucoma who had uncontrolled IOP, there was a reduction of end-diastolic flow velocities and an
increase of resistivity index in ciliary arteries and the central retinal artery (560). The color Doppler
imaging showed a significant decrease in the mean end-diastolic velocity and an increase in the mean
resistive index in all blood vessels in patients with glaucoma (561). There were no differences between
the patients with COAG and those with normal-tension glaucoma (169).
Another study, testing the reproducibility of the central retinal artery velocity measurements by using
color Doppler imaging, showed that large differences existed in measured central retinal artery velocity,
depending on the location of the measurement, and that color-flow thresholding was valuable in locating
the optimal location for pulsed Doppler spectral recording (562).
The high reproducibility of the color Doppler imaging technique for the peak-systolic and end-diastolic
velocities and for the resistance index, taken in the central retinal artery, the ophthalmic artery, and the
short posterior ciliary arteries, is suggestive to support the validity of using color Doppler imaging in a
clinical setting to measure the hemodynamic parameters of small retrobulbar blood vessels (563).
Laser Doppler Flowmetry
Laser Doppler flowmetry was introduced in 1972 to provide a noninvasive method to measure the
perfusion of ocular tissues at individual discrete locations (564). It has been used in experimental and
clinical studies (565). This technology can measure blood cell velocity in a volume of tissue and derive
an estimate of volumetric blood flow. Laser Doppler flowmetry has also been used to measure
microcirculatory blood flow in neural tissue, muscles, skin, bone, and intestine (566, 567).
The principle is to measure the Doppler shift, which is the change of frequency that light undergoes
when reflected by moving objects, such as red blood cells. Because the velocity of the red blood cells is
extremely low, compared with the speed of light, it is not possible to directly measure the resulting
alteration in the frequency or color of the light. However, laser Doppler flowmetry provides an indirect
method, in which the low-power coherent laser light that is scattered or reflected by moving red blood
cells undergoes a Doppler frequency shift, while light reflected from surrounding tissue remains in its
original frequency. The two coherent components of light, with only slightly different frequencies,
interfere and result in a phenomenon called beat. This reflected light, together with laser light scattered
from static tissue, is detected and processed to provide a blood-flow measurement. As a result, the
Doppler shift of the light frequency is translated to an intensity oscillation, which can be measured. The
laser Doppler flowmeter uses monochromatic light emitted from a low-power laser. Measurement of the
erythrocyte movement is recorded continuously in the outer layer of the tissue under study, with no
influence on physiologic blood flow. The output value is defined as the number of red blood cells times
their velocity and is reported as microcirculatory perfusion units.
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To obtain the measurement, a low-intensity laser beam is directed to a certain location of the retina and
is scanned across a tissue surface in a raster fashion using a moving mirror. The intensity of the light
reflected and scattered at that location is measured typically over several seconds. The amplitude of
measured intensity is proportional to the number of moving particles, and the frequency of the intensity
is proportional to the velocity of the particles. The results are interpreted as a frequency distribution of
the number of moving red blood cells and their velocity, providing a simple and quantitative description
of the blood flow at the selected retinal location.
Scanning Laser Doppler Flowmetry
Blood flow can be measured by combining laser Doppler flowmetry with confocal scanning laser (568,
569, 570 and 571). The method is noninvasive and results are rapidly obtained, but it requires clear
optical media and good fixation and is highly sensitive to illumination changes and eye movement; in
addition, it measures blood flow in a relatively small velocity range (572).
The Heidelberg retinal flowmeter, the model currently available, performs laser Doppler measurements
in a twodimensional array of points, resulting in two-dimensional perfusion maps. During an
examination with the Heidelberg retinal flowmeter, a laser beam enters the eye and focuses on the
retinal surface by the optical properties of the eye. The direction of the laser beam entering the eye is
periodically changed in two directions by two oscillating mirrors, so that a two-dimensional region of
the retina is scanned line by line. The scan field is 10 degrees wide and 2.5 degrees high, corresponding
to a size of 2.88 mm × 0.72 mm. During the scan along one line, the reflected light intensity at 256
pixels is measured and digitized
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sequentially. Each of the 64 total lines is scanned 128 times, with the total acquisition time of about 2.5
seconds. After the scanning is complete, for each of the 256 × 64 locations, there are 128 measurements
of the reflected light intensity versus time. When the analysis is performed at each measured location,
the result is a matrix of 256 × 64, or 16,384 pixels (perfusion map), which provides perfusion
measurements. For visualization, low perfusion values are displayed in dark colors and high perfusion in
light colors, resulting in a color-coded two-dimensional perfusion map, with the parameters of (a)
volume, (b) flow, and (c) velocity. The highest flow values occur in the larger vessels. Because of the
dual blood-flow supply in the optic nerve and the limited penetration of the laser, the instrument
primarily measures the microcirculation in the nerve fiber layer of the anterior optic nerve, which is
largely supplied by the central retinal artery rather than the ciliary circulation (573). Blood flow in the
laminar and retrolaminar regions makes only a small contribution to the measurements.
The Heidelberg retinal flowmeter has allowed demonstration in healthy volunteers that ocular blood
flow increases while inhaling carbogen and decreases while inhaling oxygen or after increasing IOP to
50 mm Hg with a suction cup (574). Although IOP values were significantly reduced by the use of
betaxolol and timolol, blood-flow values were significantly decreased only in the timolol group.
Laser Speckle Flowmetry
Laser speckle is seen when coherent laser light is scattered from a diffuse object. If instead of being
stationary the illuminated object consists of individual moving red blood cells, the speckle pattern
fluctuates randomly. The intensity of these fluctuations provides information about the velocity of the
object producing the scatter. The structure of the pattern that changes according to blood-flow velocity is
called “blurring,” and a square blur rate is an index of blood velocity, calculated by a computer.
One prospective study compared blood-flow measurements in the optic nerve head by laser speckle
flowmetry with confocal scanning laser Doppler flowmetry. There was only a weak correlation between
the blood-flow indexes, as measured by laser speckle flowmetry and scanning laser Doppler flowmetry
because of basic differences in the principles of measurement (575).
Another study has shown significant differences in optic nerve head blood flow in healthy volunteers
between the right and left eyes and between the superior and inferior temporal neuroretinal rims using
laser speckle flowmetry. These normal data may be useful in understanding the physiology of ocular
hemodynamics (576).
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Magnetic Resonance Imaging
Qualitative analysis of the perfusion of the human optic nerve with magnetic resonance imaging (MRI)
may be used to study optic nerve blood-flow abnormalities (577). MRI can also be used to quantify
changes in the optic nerve microcirculation. T2-weighted MRI in rats provided quantification of optic
nerve blood flow and has shown that dopaminergic substances increase optic nerve blood flow (578).
The Possible Future of Imaging
Exciting areas of innovation are the structural imaging of RGC bodies and the imaging of individual
ganglion cell stress and death (579, 580, 581, 582, 583, 584 and 585). These areas are still in
experimental development, but may be clinically relevant in the future.
KEY POINTS
The optic nerve head comprises axons from the RGCs, as well as blood vessels and astroglial and
collagen support. The normal optic nerve head has considerable variation in size and surface
contour.
The pathogenesis of glaucomatous optic atrophy appears to involve obstruction of axoplasmic
flow, although whether this is a direct mechanical effect of elevated IOP or secondary to vascular
changes is unclear.
Glaucomatous optic atrophy is characterized clinically by a progressive, asymmetric loss of neural
rim tissue, which is manifested by an enlargement in the area of cupping and pallor. This most
often extends in a focal direction, producing early thinning of the inferior and superior portions of
the neural rim. Enlargement of the cup often precedes that of the area of pallor, creating a pallorcup discrepancy. Other important signs of glaucomatous optic atrophy are disc hemorrhages and
peripapillary nerve fiber bundle defects.
The differential diagnosis of glaucomatous optic atrophy includes normal variations,
developmental anomalies, and nonglaucomatous causes of acquired cupping.
Techniques for evaluating the optic nerve head include a careful office examination and
photographic documentation, although newer techniques, such as computed image analysis and
blood-flow measures, may provide more precise methods of observation in the clinical
management of glaucoma.
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5 - Assessment of Visual Fields
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> Table of Contents > SECTION I - The Basic Aspects of Glaucoma > 5 - Assessment of Visual Fields
5
Assessment of Visual Fields
Advances in the technology of visual field testing have changed our clinical perception of normal and
abnormal fields of vision. For example, the two-dimensional presentation of concentric lines around the
point of fixation has given way to three-dimensional displays in symbols and numerical values.
However, the normal field of vision and the changes created by glaucoma are just the same as they were
100 years ago when Bjerrum discovered the arcuate scotoma using the back of his consulting room door
as a background for his field testing. This chapter therefore first considers the normal field of vision and
how it is altered by glaucomatous damage, and then reviews the instruments and techniques by which
these parameters can be measured.
NORMAL VISUAL FIELD
A helpful way to begin the study of visual fields and the methods by which they are measured is to
consider Traquair's classic analogy of “an island of vision surrounded by a sea of blindness” (Fig. 5.1).
This three-dimensional concept can be reduced to quantitative values by plotting lines (isopters) at
various levels around the island, or by measuring the height (sensitivity) at different points in the island
of vision.
Figure 5.1 The normal visual field (right eye) is depicted as the Traquair “island of vision surrounded by
a sea of blindness,” with projections showing the peripheral limits (A) and the profile (B). Fixation (f)
corresponds to the foveola of the retina, and the blind spot (bs) to the optic nerve head. The approximate
dimensions of the absolute peripheral boundary of the visual field and the location of the blind spot are
shown (A).
Boundaries
The shoreline of the island corresponds to the peripheral limits of the visual field, which normally
measure, with maximum target stimulation, approximately 60 degrees above and nasal, 70 to 75 degrees
below, and 100 to 110 degrees temporal to fixation (1). The typical configuration of the normal visual
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field, therefore, is a horizontal oval, often with a shallow inferonasal depression (Fig. 5.1). The shape is
usually of greater diagnostic significance than the absolute size of the visual field is, because the latter is
influenced by many physiologic and testing variables.
Contour
The peaks and valleys on the island correspond to areas of increased or decreased vision within the
peripheral limits of the visual field. These contours can be mapped by recording the weakest light
stimulus that can be seen at specific locations in the field of vision or by using test objects with reduced
stimulus value to plot smaller isopters within the absolute boundaries. The area of maximum visual
sensitivity in the normal field during photopic condition is at the point of fixation, corresponding to the
foveola of the retina, and appears as a smoothly rising peak surrounded by a high plateau (2). The visual
sensitivity
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then tapers down more gradually until it again falls abruptly at the peripheral limits.
Blind Spot
Nerve fibers, collecting visual information from the retina, come together approximately 10 to 15
degrees nasally from the fovea. This region corresponds to the optic nerve head, and because there are
no photoreceptors in this area, it creates a deep depression within the boundaries of the normal visual
field, which is called the blind spot. Because the image formed on the retina is upside down and
backward, the blind spot is located temporal to fixation. The blind spot has two portions: (a) an absolute
scotoma and (b) a relative scotoma (3). The absolute scotoma corresponds to the actual optic nerve head
and is seen as a vertical oval. Because the nerve head has no photoreceptors, this portion of the blind
spot is independent of the test object stimulus value.
The relative scotoma surrounds the absolute portion and corresponds to peripapillary retina, which has
reduced visual sensitivity, especially inferiorly and superiorly. In a study correlating the blind spot size
to the area of the optic disc and peripapillary atrophy, the absolute scotoma included the peripapillary
scleral ring and the peripapillary zone beta (see definitions in Chapter 4), whereas zone alpha was
attributed to the relative scotoma (4).
VISUAL FIELD LOSS IN GLAUCOMA
Peripheral Loss
Defects along the peripheral boundaries of the visual field (i.e., peripheral nasal steps, vertical steps, and
temporal sector defects) are most often found in association with scotomas in the more central arcuate
area, although in some patients with early glaucomatous visual field loss, peripheral defects may be the
only detectable abnormality (5, 6, 7 and 8). With automated static perimetry (discussed later), it has
become common practice to measure only the central 24 to 30 degrees of the visual field, because of the
increased time requirement with this technique. The question arises, therefore, as to how much
information is being missed by ignoring the more peripheral portions of the field. In the presence of
paracentral scotomas, peripheral measurements appear to add no significant information regarding the
progression of visual field damage (9). In the initial diagnosis, however, a peripheral field defect,
usually a nasal step, may be the only abnormality detected by automated perimetry in 3% to 11% of
patients, depending on the testing method (10, 11, 12 and 13). To be clinically useful, the time required
to obtain this information must not add excessively to the overall testing time; further study is needed to
determine whether this can be achieved with newer programs for automated perimetry.
Localized Nerve Fiber Layer Defects
In glaucoma, structural damage to ganglion cells and their axons causes partial or complete functional
loss in the area of damaged cells. The glaucomatous process typically causes initial damage to one or
more axon bundles, creating a localized visual field defect. Focal defects, due to loss or impairment of
retinal nerve fiber bundles, constitute the most definitive early evidence of visual field loss from
glaucoma. The nature of the nerve fiber bundle defects relates to the retinal topography of these fibers,
as discussed in Chapter 4.
Arcuate Defects
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Bjerrum (pronounced bee YER um) described an arcuate visual defect, which he showed is strongly
suggestive of glaucoma. This arcuate scotoma starts from the blind spot and arches above or below
fixation, or both, to the horizontal median raphe, corresponding to the arcuate retinal nerve fibers (Figs.
5.2A and 5.3). The nasal extreme of the arcuate area along the median raphe may come within 1 degree
of fixation and extends nasally for 10 to 20 degrees (14). Early visual loss in glaucoma commonly
occurs in this arcuate area, especially in the superior half, which correlates with the predilection of the
inferior and superior temporal poles of the optic nerve head for early glaucomatous damage (14, 15). As
field defects develop within the arcuate area, they most often appear first as one or more localized
defects, or paracentral scotomas (Fig. 5.2B). The typical pattern of progression of glaucomatous visual
field defects is for a shallow paracentral depression to become denser and larger (16), eventually
forming a central absolute defect, surrounded by a relative scotoma (17, 18). The relative scotoma
represents fluctuation that can be seen at the border of the physiologic blind spot and glaucomatous
defects, but is significantly larger and more sloping in the latter (19). Occasionally, the early arcuate
defect may connect with the blind spot and taper to a point in a slightly curved course, which has been
referred to as a Seidel scotoma (Fig. 5.2C). As the isolated defects enlarge and coalesce, they form an
arching scotoma that eventually fills the entire arcuate area from the blind spot to the median raphe,
which is called an arcuate or Bjerrum scotoma (Fig. 5.2D). With further progression, a double arcuate
(or ring) scotoma develops (Fig. 5.2E). The rate of visual field loss correlates with the size of the
scotoma, in that, the larger the scotoma, the more rapidly it is likely to enlarge (20).
Although the arcuate defect is probably the most reliable early form of glaucomatous field loss, it is not
pathognomonic, and the following additional causes must be considered, especially when the field and
disc changes do not seem to correlate: chorioretinal lesions, optic nerve head lesions, anterior optic
nerve lesions, and posterior lesions of the visual pathway (21, 22 and 23) (Table 5.1). At times the
arcuate defect involves the papillomacular nerve fiber bundle (Fig. 5.4).
Nasal Steps
The loss of retinal nerve fibers rarely proceeds at the same rate in the upper and lower portions of an
eye. Consequently, a steplike defect is frequently created where the nerve fibers meet along the median
raphe (Fig. 5.5). Because the superior field is involved somewhat more frequently than the inferior
portion is in the early stages of glaucoma, the nasal step more often results from a greater defect above
the horizontal midline, which is referred to as a superior nasal step. However, inferior nasal
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steps are not uncommon. Nasal steps are also distinguished by their central or peripheral location (5). A
central nasal step is created at the side of an unequal double arcuate scotoma closest to fixation. Unequal
contraction on the peripheral side of the defect, due to loss of corresponding bundles of peripheral
arcuate nerve fibers, produces a defect that has been called the peripheral nasal step of Ronne. Nasal
step often begins as an isolated scotoma in the nasal periphery (6). The shape of the peripheral nasal step
with kinetic testing differs according to its distance from fixation and is not necessarily found in all
isopters (18, 24). Nasal step appears to be a common defect in acute and early chronic angle-closure
glaucoma (25, 26).
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Figure 5.2 Arcuate nerve fiber bundle defects. A: The arcuate (or Bjerrum) area is shown within the
dotted lines. B: Superior paracentral scotoma, with central absolute defect surrounded by a relative
scotoma. C: Seidel scotoma. D: Complete arcuate (Bjerrum) scotoma. E: Double arcuate (ring) scotoma
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with superior central nasal step. F: Vertical step (or hemianopic offset).
Figure 5.3 Grayscale of a SITA standard 24-2 achromatic visual field showing superior arcuate defect
with corresponding inferior neuro-retinal thinning and retinal nerve fiber layer thinning.
Table 5.1 Differential Diagnosis of Arcuate Scotomas
Chorioretinal lesions
Juxtapapillary choroiditis and retinochoroiditis
Myopia with peripapillary atrophy
Retinal pigment epithelium and photoreceptor degeneration
Retinal artery occlusions
Optic nerve head lesions
Drusen
Retinal artery plaques
Chronic papilledema
Papillitis
Colobomas (including optic nerve pit)
Anterior optic nerve lesions
Carotid and ophthalmic artery occlusion
Ischemic infarct
Cerebral arteritis
Retrobulbar neuritis
Electric shock
Exophthalmos
Posterior lesions of the visual pathway
Pituitary adenoma
Opticochiasmatic arachnoiditis
Meningiomas of the dorsum sella or optic foramen
Progressive external ophthalmoplegia
Pseudotumor cerebri
Vertical Step
A stepwise defect along the vertical midline, referred to as a vertical step (Fig. 5.2F) or hemianopic
offset, is a less common feature of glaucomatous field loss than the nasal step is; it occurs in roughly
20% of cases (27, 28). The mechanism of this field defect is not fully understood, although it may relate
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to segregation in the optic nerve head of axons from either side of the vertical midline (27). The defect
more often appears on the nasal side of the vertical midline (Fig. 5.6). However, healthy eyes have also
revealed greater sensitivity temporal to the hemianopic border, and it has been suggested that a small
peripheral step at the vertical midline should arouse suspicion of glaucoma only if the defect is located
temporally (29). It also has limited diagnostic value because most are associated with other
glaucomatous field changes (28), and the main significance of the observation is in distinguishing
glaucomatous vertical midline defects from those caused by neurologic lesions.
Generalized and Central Depression of the Visual Field
The increased sensitivity with which newer instruments allow evaluation of vision is changing our
understanding of the natural history of progressive visual field loss in glaucoma. Although defects
related to loss of retinal nerve fiber bundles are the most familiar visual field changes induced by
glaucoma, and central vision is typically one of the last regions to be totally lost, studies have shown
mild central and diffuse reduction in the visual field even in the early stages of glaucoma (30, 31, 32, 33,
34 and 35). The mechanism for this is uncertain, although it appears to represent pressure-induced
damage with diffuse nerve fiber loss, as evidenced by abnormal light-sense and flicker perimetry, which
have been shown to accompany diffuse retinal nerve fiber layer (NFL) loss (33, 34, 36, 37).
Central vision is typically preserved in the early course of glaucoma, but rarely it may be affected by a
localized damage involving the fixation point. In these situations, other visual functions, such as visual
acuity and color vision, may become abnormal. These central defects should be differentiated from
macular disorders.
Although most studies agree that some patients with early glaucoma can have purely diffuse loss in the
absence of other causes, other investigators have challenged this concept, suggesting that a generalized
depression in glaucoma is rare and that these patients may have other causes for the diffuse loss of
perimetric sensitivity, such as media opacity, miosis, or retinal dysfunction (30, 31 and 32, 34, 38, 39,
40, 41 and 42). In any case, the diagnostic value of this finding is currently limited by its nonspecific
nature, but it should still be looked for and noted in the course of visual field testing and analysis.
Although the measures of generalized reduction in visual function may one day be important in the early
detection of glaucoma, they are too inconsistent and nonspecific at present to be of highly significant
clinical value. In the future, they may acquire greater diagnostic significance as our knowledge of
glaucomatous visual dysfunction expands. The following are some of the perimetric and other measures
that can be used to evaluate generalized visual impairment in glaucoma.
Concentric Contraction
Generalized reduction in the visual field may become manifest as a decrease in sensitivity for specific
retinal locations or as a concentric constriction of the visual field, both of which precede other detectable
glaucomatous field defects in many patients (43, 44). Isopter contraction, as an early field defect of
glaucoma, is often more marked in the nasal field, which has been called “crowding of the peripheral
nasal isopters” (45).
Enlargement of the Blind Spot
Enlargement of the blind spot, due to depression of peripapillary retinal sensitivity, is also considered to
be an early glaucomatous field change. However, it may be seen with other optic nerve or
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retinal disorders. One example has been called “acute idiopathic blind spot enlargement” and is related
to multiple evanescent white-dot syndrome and possibly other retinal diseases (46, 47 and 48).
Enlargement of the blind spot can also be produced in healthy persons with threshold targets, so that it is
not a pathognomonic sign of glaucoma (49). The relative portion of the blind spot depends on the
stimulus value and varies with different testing methods. If the temporal margin of the relative blind spot
comes close to the corresponding isopter (in kinetic perimetry), the two boundaries may artifactually
become confluent, creating false baring of the blind spot. In addition, because the reduced sensitivity of
the peripapillary retina is greater in the upper and lower poles, test objects with small stimulus value
may cause vertical elongation of the blind spot, which can break through the isopter, causing true baring
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of the blind spot (Fig. 5.7).
Figure 5.4 Grayscale of a SITA standard 24-2 achromatic visual field showing an arcuate defect
involving the papillomacular nerve fiber bundle. The corresponding optic nerve with extensive temporal
thinning and peripapillary atrophy. HRT-II Moorfields regression analysis calling attention to the
temporal rim.
Angioscotomata
Angioscotomata are long, branching scotomas above and below the blind spot, which are presumed to
result from shadows created by the large retinal vessels. Retinal vessels may
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have corresponding representation of angioscotomata in the visual cortex (50). Angioscotomata may
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represent an early glaucomatous field defect, although it is technically difficult to demonstrate and not
highly diagnostic (51, 52, 53 and 54).
Figure 5.5 Grayscale of a SITA standard 24-2 achromatic visual field showing a nasal step. Optic nerve
demonstrates significant inferior thinning, which is also called to attention by the HRT-II Moorfields
regression analysis.
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Figure 5.6 Grayscale of a SITA standard 24-2 achromatic visual field showing a vertical step.
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Figure 5.7 False baring (A) and true baring (B) of the blind spot.
Temporal Sector Defect
Because the retinal nerve fibers nasal to the optic nerve head converge on the disc by a direct route, a
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lesion involving these fiber bundles produces a sector defect temporal to the blind spot (18, 24) (Fig.
5.8). This defect usually appears later in the course of glaucomatous field loss (55), but can be the
presenting visual field defect. With automated perimetry, glaucomatous defects temporal to the blind
spot are not uncommon, but usually add significant information beyond findings of central field testing
only in patients with late visual field loss (56).
Advanced Glaucomatous Field Defects
The natural history of progressive glaucomatous field loss involves the eventual development of a
complete double arcuate scotoma, which coalesces nasally at the horizontal meridian (57) and may
extend to the peripheral limits in all areas except temporally. This results in a central island and a
temporal island of vision in advanced glaucoma. With continued damage, these islands of vision
progressively diminish in size until the tiny central island is totally extinguished, which may occur
abruptly. Glaucoma surgery appears to accelerate the loss of the small central island in some patients,
possibly because of the sudden change in intraocular pressure (IOP), although this complication does not
occur frequently enough to constitute a contraindication to surgery in these patients (58). The temporal
island of vision is more resistant and may persist long after central vision is lost. However, it, too, will
eventually be destroyed if the glaucoma is not controlled, leaving the patient with no light perception.
Figure 5.8 Grayscale of a SITA standard 24-2 achromatic visual field showing a temporal wedge defect.
Visual Field Changes in Normal-Tension Glaucoma
The nature of visual field defects may be influenced by the IOP, although reports on this are somewhat
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conflicting. In one study of patients with chronic open-angle glaucoma (COAG) who had early visual
field loss, persons with diffuse depression had higher pressures than those with localized defects did (59)
(Fig. 5.9). In addition, in some studies patients with COAG whose IOP has never exceeded
approximately 21 mm Hg, commonly referred to as normal-tension (or low-tension) glaucoma, had
scotomas with steeper slopes, greater depth, and closer proximity to fixation, compared with patients
with COAG who had higher IOPs (60, 61). In other studies, however, these two groups did not differ
significantly when the same degree of optic nerve damage was present (62, 63). Another study of
normal-tension and high-tension glaucoma patients whose automated visual fields were matched to
within a 0.3-dB mean deviation (explained later) revealed no significant difference in focal defects in the
overall field or superior hemifield, but did show significantly more localized loss in the inferior
hemifield among the normal-tension patients, supporting the hypothesis of a vascular mechanism in that
group (64).
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Figure 5.9 Grayscale of a SITA standard 24-2 achromatic visual field showing a paracentral defect from
a patient with low-tension glaucoma. The optic nerve photograph demonstrates a corresponding notch
inferiorly.
One study investigated the effect of trabeculectomy on the rate of visual field progression in patients
with normal-tension glaucoma. The authors concluded that surgical lowering of IOP resulted in a
decreased rate of visual field loss in the operated eye (65).
The Collaborative Normal-Tension Glaucoma Study investigators also concluded that IOP reduction
decreases glaucoma progression in normal-tension glaucoma (66).
Visual Field Changes with Acute Pressure Elevation
The preceding discussions have dealt with field changes that are associated primarily with chronic forms
of glaucoma. When the IOP elevation is sudden and marked, as in acute angle-closure glaucoma, various
associated field changes have been reported, including general depression, early loss of central vision,
arcuate scotomas, and enlargement of the blind spot (67). After the acute attack is brought under control,
the fields return to normal in some patients, but other patients may have reduced color vision,
generalized decreased sensitivity, or constriction of isopters, especially superiorly (68).
When the IOP is artificially elevated, by compression of the globe or administration of topical steroids,
typical glaucomatous field defects or constriction of central isopters occur in some eyes (69, 70, 71, 72,
73, 74 and 75). The changes are reversible when the IOP returns to normal and are dependent on the
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ocular perfusion pressure (73, 74, 76). This response to artificial pressure elevation is said to occur more
commonly in patients with glaucoma (69, 70, 76)—especially normal-tension glaucoma (67)— although
one study found no difference between patients with and without glaucoma (71).
Correlation between Optic Nerve Head and Visual Field Defects
In most patients with glaucoma, clinically recognizable disc changes precede detectable field loss, and
the presence or absence of glaucomatous field defects can usually, but not always, be predicted from the
appearance of the optic nerve head (77, 78, 79, 80, 81 and 82). Quigley and coworkers (83, 84)
attempted to correlate axon loss in the optic nerve head with visual field defects. Although limited by
small sample size, their work suggested that not only does nerve fiber loss occur before reproducible
field defects in some patients with elevated IOP, but the extent of axonal loss may be much greater than
the corresponding visual field change. With standard perimetric techniques, 25% to 35% of the retinal
ganglion cells may be lost in an eye with a normal field by the time reproducible early field defects are
found (85), and 10% or fewer axons may remain by the stage of severe field loss (83). When correlating
retinal ganglion cell atrophy with automated perimetry in patients with glaucoma, a 20% loss of cells,
especially large ganglion cells in the central 30 degrees of the retina, correlated with a 5-dB sensitivity
loss (discussed later), whereas a 40% loss corresponded with a 10-dB decrease, and some ganglion cells
remained in areas with 0-dB sensitivity (84).
The nature of optic nerve head cupping can also be used to predict the type (in addition to the presence)
of field loss. Extensive or focal absence of neural rim tissue, especially at the inferior or superior poles,
is the most reliable indicator of visual field disturbance and is usually associated with a field defect in
the corresponding arcuate area (79, 86, 87, 88 and 89). In some eyes, field loss may occur before the
pallor reaches the disc margin (86), and unusual cases have been reported with field damage despite
round, symmetric cups (79). Quantitative measures of the retinal NFL also correlate with the visual field
loss in patients with glaucoma (90).
The ability to predict impending glaucomatous visual field loss by the appearance of the optic nerve
head is less accurate than correlating disc damage with established field loss. No single parameter or
combination of parameters in glaucomatous optic atrophy is totally satisfactory for this purpose. The
parameters that correlate best with visual field loss are magnification-corrected measurements of
neuroretinal rim area and defects in the retinal NFL (91, 92, 93, 94, 95, 96, 97, 98 and 99). Diffuse
structural changes in the optic nerve head or retinal NFL are more often associated with diffuse
depression of visual function, whereas localized changes correlate more with localized visual field
changes (98). In some cases, the early field loss associated with retinal NFL defects can be detected with
automatic perimetry when it has been missed with manual perimetry (100, 101).
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The correlation between optic nerve head and visual field defects in glaucoma is close enough to prompt
a search for other underlying disease processes, such as neurologic disorders, if a correlation is not
found. Nevertheless, the absence of a perfect correlation indicates that both disc and field examinations
are essential in managing the glaucoma patient (102). In general, optic nerve head and retinal NFL
changes have their greatest value in the early stages of glaucoma, whereas progressive visual field loss
becomes the more useful guide to therapy in advanced cases (77, 103).
BASIC PRINCIPLES OF VISUAL FIELD TESTING
Stimuli
The typical stimuli used in clinical perimetry are spots of light of various predefined combinations of
diameter and intensity projected on the background. The visibility of the stimulus also depends on how
far the eye is positioned from the screen and the brightness of the background. The other factors
affecting perception of the stimulus include the length of time the stimulus is presented, the color of the
stimulus and the background, whether kinetic or static techniques are used, and the condition of the eye
and the patient.
The absolute light intensity is measured in units of luminance, called apostilbs, but the measured light
sensitivity is expressed in logarithmic units referred to as decibels (dB), which provides a more linear
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relationship between visual perception and a change in light intensity. A decibel is 0.1 log-unit, so that a
10 dB represents a 10-fold decrease of the maximum stimulus of any specific perimeter, and a 20 dB
represents a 100-fold stimulus attenuation. The maximum intensity of a perimeter has a value of 0 dB,
meaning that the stimulus is not attenuated. Log-units and decibels are relative units, and resulting
stimulus intensity is not the same for all instruments, but decibels represent the same percentage change
of the intensity in all perimeters.
Stimulus Size
The standard target for kinetic and static perimetry is a white disc, the stimulus value of which can be
adjusted by varying the target size or luminosity relative to that of the background. In healthy persons,
the mean retinal sensitivity has been shown to increase with the increasing size of the test object (104).
If the diameter of the smaller stimulus is increased, it may be as visible as the less intense larger
stimulus, the phenomenon known as spatial summation. Usually, doubling the stimulus diameter has the
same effect on the visibility of the stimulus as increasing its intensity by 5 dB (1).
Exposure Time
The exposure time will also affect the stimulus visibility. The stimulus presented over a longer period of
time may become more visible, the phenomenon called temporal summation. However, after the
temporal summation is complete, which happens typically after 0.1 second, the image is not seen any
better. The Humphrey field analyzer uses a 0.2-second stimulus duration, which also helps prevent
movement of the patient's gaze toward the stimulus. However, suprathreshold static targets should be
presented for a longer time, usually 0.5 to 1 second, and test objects should be just above threshold for
the area being tested.
Kinetic versus Static Perimetry
The threshold is theoretically the target that is just bright enough to be seen 50% of the time at that
location (the differential light threshold). The stimulus that is below the threshold value cannot be seen.
Kinetic perimetry defines threshold by moving the test object from a nonseeing (subthreshold) to a
seeing (suprathreshold) area, and by recording the point at which it is first seen in relation to fixation
(Fig. 5.10A). The procedure documents the boundaries of the visual field for the absolute limits and
areas of relative differences in visual acuity within the field (Fig. 5.11). As previously noted, the
boundaries, or contour lines, are called isopters. The size and shape of a particular isopter depend partly
on the stimulus value of the corresponding test object.
Static perimetry involves the presentation of stationary test objects, by using suprathreshold or threshold
presentations. Suprathreshold static presentation is an “on-off” technique in which a test object just
above the anticipated threshold for the corresponding portion of the visual field is momentarily
presented, and the points at which the patient fails to recognize the target are noted as visual field
defects. It is a way of “spot checking” for areas of relative or absolute blindness, usually in the central
visual field. The suprathreshold strategy is used mostly as a screening test.
Threshold static perimetry measures the relative intensity thresholds for the visual acuity of individual
retinal points in the field of vision. The technique involves gradually increasing the target light from
subthreshold intensity in small increments, and recording the level at which the patient first indicates
recognition of the target (Fig. 5.10B), or decreasing
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it from a suprathreshold level and recording the lowest stimulus value seen. The points are tested at
predefined locations throughout the visual field, and the results are recorded as grayscale symbols and
numerical sensitivity values in decibels (Fig. 5.12).
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Figure 5.10 Standard techniques for measuring the visual field. In kinetic technique (A), test object
moves from nonseeing to seeing area. Static technique (B) measures sensitivity of retina at a given point.
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Figure 5.11 Example of manual kinetic perimetry showing two complete isopters (l2 and l4) and a third
partial isopter (V4) in nasal periphery with blind spot measured by l2 target.
The kinetic stimuli are usually seen better than the static ones are, but when the stimulus is moved
slowly, the results of kinetic and static perimetry are similar.
To minimize the patient's anticipation of when or where the next test object will appear, the presentation
should be random, rather than following a predictable pattern, and the time between stimuli should be
varied slightly. To avoid patient anxiety when testing in a nonseeing area, the examination should return
periodically to a previously seen area.
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Figure 5.12 Examples of threshold static (standard automated) perimetry. Retinal sensitivity is measured
at points throughout a portion of the visual field (central 24 to 30 degrees in this example). Results can
be displayed in numerical values and symbols.
For kinetic targets, a stimulus velocity of 4 degrees/sec appears to be optimal for all targets in the central
and peripheral visual field, but a slower velocity of 2 degrees/sec may provide more reproducible results
in some patients (105, 106). The test object should always be moved from a nonseeing to a seeing
area—that is, from the periphery toward fixation when outlining an isopter and from the center of the
blind spot or a scotoma.
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Threshold static perimetry has been shown to be more sensitive than kinetic perimetry is in detecting
glaucomatous field loss (107, 108). In one study of patients with COAG, a defect was found in one third
of the cases with static perimetry that was missed by kinetic perimetry (109). In a long-term study of
patients with ocular hypertension, 75% of those who developed glaucomatous damage had an
abnormality detected by automated static perimetry (by using a hemifield test, explained later) 1 year
before field loss was detected by manual perimetry, by using a combination of kinetic and static
presentations (110).
When automated static perimetry was compared with Goldmann kinetic perimetry as a test for driving, a
significant number of patients with severe field defects, detected by static perimetry, still met the
standard for driving by the kinetic perimetry (111).
Because standard static threshold perimetry tests sensitivity near threshold, patients do not see
approximately half the presented stimuli, and they may report that stimuli are too dim to see. Patients
should be told that the limits of their seeing abilities are being tested and that barely seeing the stimuli is
natural.
Background Illumination
Background illumination for manual perimetric techniques traditionally stimulates both rods and cones.
The adapting field luminance currently used in static and kinetic perimetry is marginally photopic (e.g.,
31.6 apostilbs), although the optimum luminance has yet to be established. One study suggested that the
lower levels of background illumination may allow minor reductions in light transmission by the ocular
media to produce significant changes in the recorded threshold sensitivity (112). In a comparison of
scotopic and photopic fields, localized scotomas in patients with glaucoma were of equal depth, but
diffuse scotopic defects significantly exceeded the photopic, supporting the concept that not all ganglion
cell types are equally susceptible to glaucomatous damage (113). Scotopic defects were also found more
often in patients with ocular hypertension or glaucoma than in healthy persons, and the defects were
mainly in the superior hemifield (114).
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With bowl perimeters, photometric adjustment should be made with the patient in place, because facial
coloring affects luminosity. The most important principle regarding illumination is to keep the target and
the background constant and reproducible from one examination to the next.
Physiologic Influences on Visual Fields
The following factors should be compensated for, if possible, or otherwise should be considered when
interpreting the fields.
Pupil Size
Although decreased pupil size should have little effect on a patient's perception of a stimulus, because
background and stimulus are affected equally, significant miosis may depress central and peripheral
threshold sensitivities and exaggerate field defects (115), even after correction of induced myopia (116).
One study used neutral density filters to reduce the retinal illumination by the equivalent of halving the
pupillary diameter, which reduced the mean threshold with two automated perimeters by 1.1 to 1.7 dB
(117). In another study, use of pilocarpine worsened the visual field global indices, such as mean
deviation and pattern standard deviation (explained later) (118). For this reason, the pupil size should be
recorded with each field, and the influence of miosis should be considered when a field change is
detected. Mydriasis has less influence on the visual field than miosis does, although pupillary dilatation
with use of tropicamide, 1%, or no ocular medication in healthy persons reduced threshold sensitivity
with automated perimetry in one study (119).
Age
Increasing age is also associated with reduced retinal threshold sensitivity (120). This effect starts as
early as 20 years of age, progresses linearly throughout life, and involves the peripheral and superior
areas more than the pericentric and inferior portions of the field (121, 122). This age-related visual field
sensitivity appears to be primarily due to neural loss rather than preretinal factors (123). Standard
automated perimetry (SAP) protocols compensate for the effect of age by using age-bracketed databases.
Clarity of Ocular Media
Cataracts produce glare and change the intensity of the stimulus. Therefore, a cataract can cause or
exaggerate central or peripheral field defects, which could be mistaken for the development or
progression of glaucomatous field loss. Even minimal light scattering, as may be caused by an early
cataract that has a relatively insignificant effect on visual acuity, may influence threshold measurements
(124). As previously noted, this effect may be greater with lower levels of background illumination
(112). Eyes with COAG and cataracts may have improvement of foveal sensitivity, visual field scores,
and sometimes even a reversal of a partial or complete scotoma after cataract extraction (125, 126 and
127). However, cataract surgery can also reveal mild and moderate field defects masked by cataracts
(128, 129). Nuclear cataracts depress central perimetric sensitivity more than peripheral sensitivity with
both large and small targets, whereas nonnuclear cataracts influence central sensitivity more for small
targets and peripheral sensitivity more for large targets (130). Attempts have been made to correlate
visual field damage with lens opacity and visual acuity to aid clinicians in determining the significance
of field change in patients with glaucoma and cataracts (131, 132).
Reduced clarity of the ocular media from other causes, such as a corneal disturbance, a cloudy posterior
lens capsule after cataract surgery, or vitreous opacities, may also affect the visual fields. Applanation
tonometry before automated static threshold perimetry was found to have no detrimental effect on the
visual field results (133).
Refractive Error and Retinal Blur
When the projected stimulus is not focused on the retina, the edge of the stimulus is blurred, contrast is
decreased, and the stimulus may not be detected by the patient. The larger
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the stimulus, the less it is to be affected by the blur. Refractive errors primarily influence the central
field (134). When a standard size III stimulus is used, refractive errors of 1 diopter (D) or less may not
need to be corrected, because it usually will cause only slightly more than 1 dB of general reduction of
sensitivity (135). Mild myopia requires no correction, unless the refractive error exceeds 3 D. Posterior
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staphylomas can create areas of relative myopia, called refraction scotomas, which may be confused
with glaucomatous field defects, but can usually be eliminated with an appropriate refractive correction.
Hyperopia has a greater influence on perimetric results, especially for the central field, and even small
hyperopic refractive errors can significantly alter threshold sensitivity (134, 135 and 136). Age tables are
available to aid in determining the appropriate correction for presbyopia. A contact lens provides the
best correction for the aphakic and highly myopic eyes (137), although spectacle correction can be used
for the central 24 to 30 degrees with no correction for the peripheral field. Astigmatism should be
corrected unless the cylinder is less than 1 D, in which case it can be included as the spherical
equivalent.
Psychological Influences on Visual Fields
Patients' understanding of the test and their alertness, concentration, fixation, and cooperation all affect
the results of visual field testing (138). A learning effect with automated perimetry may influence the
results of a patient's first or second field test, suggesting that an initial field that does not agree with the
clinical findings should be repeated (139, 140 and 141). One study found that patients with refractive
errors, especially those with myopia, had a larger learning effect than patients with emmetropia did
(142). Another study found that moderate alcohol intake did not influence differential light sensitivity as
tested by automated perimetry (143). With manual perimetry, the skill of the perimetrist influences the
visual field test results (144).
Patient Fatigue
Full-threshold protocols take a long time to complete, and patients usually find visual field testing
exhausting. Fatigue causes artificially decreased sensitivity in the areas of existent glaucomatous defect
(145). Fatigue may also cause decreased performance in patients with glaucoma within central 10
degrees, and increased deterioration of the mean defect and localized loss in the periphery (146, 147).
TECHNIQUES AND INSTRUMENTS FOR MEASURING THE FIELD OF VISION
Just as a cartographer maps the boundaries and topography of an island, so the perimetrist can measure
both the peripheral limits of a visual field and the relative visual acuity of areas within those limits. This
may be accomplished by using static or kinetic techniques with instruments that are computer assisted
(automatic) or manually operated.
Automated Static Perimetry
Automated perimetry is accepted as the standard way of measuring the visual field. The standard
protocol of static white-on-white stimuli is commonly known as SAP. A major limitation of tangent
screens and arc perimeters (discussed later) was lack of standardization of the test objects and the
background, and patient fixation. These needs were addressed in the era of standardization, which began
in the middle of the 20th century with the contributions of Goldmann. The main problem that remained,
however, was the subjectivity of the patient and the perimetrist. Although subj ectivity of the patient has
not been eliminated, the influence of the perimetrist was eliminated to variable degrees with the advent
of automated perimetry in the 1970s. A wide variety of automated perimeters have been designed since
then. Many of these are no longer commercially available, but current models represent modifications of
the originals.
By reducing the influence of the perimetrist, automated perimetry improves the uniformity and
reproducibility of visual fields. With these instruments, the perimetrist only ensures that the patient
understands the testing procedure, is comfortably positioned at the perimeter, and adheres to the
requirements of the test. In addition, the use of computers has provided new capabilities that are
impossible with manual perimetry, including random presentation of targets, estimations of patient
reliability, reduced variability, and statistical evaluation of data at many levels. With the recent
introduction of efficient threshold strategies, automated perimetry is not only more accurate and
informative but is also faster than manual perimetry.
Basic Components of Automated Perimeters
Automated perimeters have two main components: the perimetric unit and the control unit. The
perimetric unit in most systems uses a bowl-type screen, similar to that of the Goldmann manual
perimeter (discussed later).
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The control unit provides interaction between the operator and the computer through a dialogue screen
and a keyboard or light pen. The computer in the control unit provides and monitors instrumentation
function according to the perimetrist's request, evaluates the patient's response, and processes data. The
control unit also contains a printer, which provides a hard copy of the data in symbols and numeric
values. Computers also store recorded information and can perform statistical analyses of the data in
relation to the programmed normal database, or against previous fields for the same patient.
Static targets are used in most automated perimeters. Automated kinetic targets have also been evaluated
and are provided on some automatic perimeters, although rarely used today, probably because of the
high frequency of fixation errors and longer testing time (11, 12 and 13, 106, 148, 149). The targets may
be projected onto the bowl, which is the current standard, or illuminated from light-emitting diodes
(LEDs) or fiber optics in the perimetric bowl in earlier models. The former has the advantage of
unlimited presentation locations on the screen, whereas the latter two have fixed positions in the bowl.
In addition, the LEDs
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were recessed in dark cavities, which may allow perception by the most sensitive retinal areas of a
stimulus that is of lower intensity than the background light (150, 151). This “dark hole phenomenon” is
associated with increased variability in retesting the threshold (150, 151). Projected targets also have the
advantage of allowing for change in size to alter the stimulus values. In practice, the size is usually kept
constant, although larger targets may permit the measurement of visual function in areas that had been
considered absolute scotomas with standard-sized stimuli (152). A larger target (size V stimulus) was
found to be useful in patients with end-stage glaucoma (153). With all target systems, the patient usually
presses a button to indicate when a target is seen, which is recorded by the computer.
The standard stimulus in most automated perimeters is a white light on a white background, which tests
the patient's differential light sense.
Commercial Units
The first of the full-threshold perimeters to receive extensive study was called the Octopus. With each
Octopus model, stimuli are projected onto a bowl, and fixation is monitored by the corneal light reflex
method and a television view of the patient's eye. The models differ primarily according to computer
capabilities. These automated perimeters were shown in early studies to compare favorably with manual
perimetry and to frequently detect field loss missed with the Goldmann perimeter (154, 155 and 156).
The Humphrey field analyzer and Humphrey field analyzer II also use projected stimuli on a bowl (Fig.
5.13). They monitor fixation by the Heijl-Krakau periodic blind spot check method and also by corneal
light reflex in newer models. It is currently the most commonly used automated perimeter. It has also
compared favorably with manual perimetry on the Goldmann perimeter, often detecting defects that the
latter missed (157). In one study, however, patients preferred the Goldmann perimeter, whereas the
technician favored the Humphrey (158). The Octopus and Humphrey units have been compared in
several studies. In one study, both short- and long-term fluctuations (explained later) were greater with
the Octopus (159). In another study, both automated perimeters identified slightly more defects by
meridional threshold testing than the Tübingen manual perimeter did (160) (discussed later).
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Figure 5.13 Humphrey Field Analyzer (HVAII). (Courtesy of Carl Zeiss Meditec, Inc.)
Test Patterns
A broad menu of test patterns is available with most instruments. The most commonly used are limited
to the central 24 to 30 degrees, with a 6-degree separation between test locations. The 6-degree grid may
miss the physiologic blind spot and small glaucomatous defects in a high percentage of cases, and it has
been suggested that tighter grids should be used, especially in the central 10 to 28 degrees (161, 162 and
163). Special programs are available to study smaller portions of the field with tighter grids. Programs
are also available to study the peripheral field beyond 30 degrees in the nasal quadrant or for 360
degrees. The peripheral studies can be performed alone or in conjunction with a central field program
and usually have wider target separation. Static testing of the peripheral nasal field has been shown to
provide valuable additional information in detecting glaucomatous defects (164). Automated kinetic
measurement of the peripheral field, especially nasally, was also found to provide useful information in
many patients, in addition to the information obtained from central testing (11, 12 and 13). One study of
various factors that affect the reaction time during automated kinetic perimetry led to the suggestion that
the test should be designed to adjust to individual patient responses, because other factors, such as
eccentricity or luminance level, were found to have much smaller effect on reaction time within the
central 30 degrees (106).
Testing Strategies
All fully automated perimeters take advantage of computer capabilities by using random presentation of
the static targets to avoid patient anticipation of the next presentation sites. In addition, an adaptive
technique is used, in which stimuli are presented according to the presumed normal retinal threshold
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contour (i.e., the relative differential light thresholds throughout the visual field), on the basis of agecorrected normal data or the patient's response to preliminary spot tests (Fig. 5.14). This approach, in
comparison with the presentation of a constant stimulus value throughout a portion of the field, as with
many manual techniques, improves the balance between sensitivity (the ability to detect defects) and
specificity (the ability to detect normal areas). Fully automated perimeters provide suprathreshold and
full-threshold measurements.
Suprathreshold Static Perimetry
Suprathreshold static perimeters present a stimulus brighter than the anticipated normal value for the
corresponding retinal location. Some instruments simply indicate whether the target was seen, whereas
others present a second, high-intensity target in nonseeing areas to distinguish between relative and
absolute defects. In either case, however, these instruments are limited
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to screening functions, in that they do not provide sufficient information about the depth or contour of a
field defect to be used as a baseline study or for following up the patient during therapy. With the
continued advances in automated perimetry, these suprathreshold strategies have been largely replaced
by full-threshold strategies, although suprathreshold models may have value as screening devices.
Improved algorithms have been suggested to improve performance of suprathreshold perimetry (165,
166).
Figure 5.14 Adaptive strategy used in automated static perimetry. A: When a constant luminosity is
presented throughout a portion of the visual field, true defects near fixation may be missed (falsenegative), whereas more peripheral normal areas may be read as abnormal (false-positive). B: The
adaptive strategy minimizes this by changing the stimulus value according to the retinal threshold
contour. With full threshold programs, the retinal threshold is crossed by increasing or decreasing the
stimulus value (1) and is then crossed a second time with smaller increments of change in luminosity
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(2).
Full-Threshold Perimetry
Threshold static perimeters are capable of various testing strategies in addition to suprathreshold
screening. The most commonly used programs measure the retinal threshold at 70 to 80 points within
the central 24 to 30 degrees. A suprathreshold target is first presented, and the luminosity is then
gradually increased or decreased until the patient's threshold is crossed—that is, the target comes into or
goes out of view, respectively. The threshold is then crossed a second time with smaller increments of
change in luminosity to refine the threshold determination. Many programs continuously adjust
subsequent stimulus values according to prior measurements; for example, the level is increased when
testing near a known scotoma on the basis of optimized algorithms. Special programs have been
evaluated that automatically increase the density of test locations around defective areas, although the
value of this approach has yet to be established (167, 168). Other programs are designed to reduce
testing time by adjusting the initial target values according to previous fields by the same patient or by
thresholding only locations that are missed with the suprathreshold target. The latter strategy, when
compared with full-threshold programs, reduced the testing time by as much as two thirds but missed
some defects that were detected with full thresholding (169, 170).
Other Threshold-Testing Algorithms
FASTPAC. Another thresholding strategy to reduc testing time is the FASTPAC program of the
Humphrey field analyzer, which estimates thresholding from a single threshold crossing in 3-dB
increments, in contrast to the standard double threshold crossing with 4 and 2 dB. This strategy has been
evaluated by several investigative teams, most of whom agree that it provides time reduction at some
expense of accuracy and reliability (171, 172, 173 and 174).
Swedish Interactive Threshold Algorithm (SITA). In recent years, the relatively new threshold strategy
known as SITA has become increasingly popular (175, 176, 177, 178, 179, 180, 181 and 182). This
algorithm uses standard 24-2 or 30-2 patterns to assess the visual field on the basis of the probability
analysis of the patterns of glaucomatous damage; it is more time efficient than standard threshold
strategies. It significantly minimizes test time without significant reduction of data quality. Two versions
of SITA are currently available: SITA Standard and SITA Fast. SITA Standard takes approximately half
the time to complete, compared with the standard full-threshold program, and SITA Fast takes about
half the time of the FASTPAC algorithm. SITA requires significant computer power during the test and
is available only on newer Humphrey visual field analyzers.
SITA uses new concepts, such as visual field modeling, that utilizes frequency-of-seeing curves for
patients with and without glaucoma. During the SITA test, a computer also produces an information
index, which stops the test at the location being examined when threshold reaches a preselected level.
The SITA method also makes more individual adjustments to patient response time. After the test is
complete, the program makes additional, more precise recalculation of all thresholds measured and
produces estimates of false-positive and false-negative response rates (1). One retrospective study found
that defects assessed with SITA were often more pronounced, when compared with standard fullthreshold perimetry, but there were essentially no significant differences in quality. Average time
reduction by SITA Standard depended on the severity of glaucomatous stage. No significant time
difference was found for advanced glaucoma, whereas normal fields using SITA were performed in half
the time of full-threshold strategy. The reduction of test time reduces the fatigue factor and permits more
frequent visual field examinations and thus a better detection of early glaucoma or progressing visual
field damage (183).
Tendency-Oriented Perimetry (TOP). TOP is another fast strategy algorithm available on new Octopus
perimeters (184, 185). It also uses a computational approach to estimate threshold values by
extrapolating information from surrounding test points. One study compared SITA Fast and TOP
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technologies, and found that the mean testing time for the TOP strategy was slightly more than 2.5
minutes, compared with approximately 4 minutes for SITA Fast (186). However, another report
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suggested that the TOP algorithm may not be able to spatially localize defects and accurately estimate
sensitivity of visual field defects (187).
Patient Fixation
Patient fixation is monitored in various ways depending on the sophistication of the instrument. Some
use a telescope, similar to the Goldmann manual perimeter, whereas others allow the operator to observe
the patient's eye on a television screen. Automatic fixation monitoring is also incorporated into most
units either by periodically retesting the patient's response in the previously determined blind spot (the
Heijl-Krakau method) or by monitoring a light reflex from the patient's cornea. With the latter method,
the computer can be programmed to stop the test whenever fixation is lost. Fixation is important,
because eye movement has been shown to increase local short-term fluctuation and false-negative rates
(188). However, maintaining fixation is difficult for many patients, and a new strategy of kinetic
fixation, in which the fixation target is moved between stimuli, has been shown to improve threshold
sensitivity (189). On the other hand, another study has found that kinetic fixation was associated with
inaccurate fixation and underestimation of the absolute scotoma at the physiologic blind spot (148). New
perimeters also use gaze tracking devices, which allow monitoring of the patient's gaze during the test.
Interpreting the Results and Analyzing Progression
Determining Test Reliability
Several strategies are used to document variability and reliability of test results. With most fullthresholding programs, a percentage of random locations are retested to determine the reproducibility at
those points. As noted earlier, these variations are referred to as short-term fluctuation and are expressed
as the square root of the variance. The patient's general reliability is assessed with a series of falsepositives (patient responds when no target is presented) and false-negatives (patient does not respond to
a stimulus of maximal intensity where a stimulus was previously reported to be seen), as well as the
frequency of fixation losses and the number of stimuli required to complete the test. This current
strategy of reliability indices has several problems. With the exception of the number of stimuli, all
reliability parameters add to the testing time, which may actually reduce the patient's reliability.
Furthermore, because each represents a limited sampling, the usefulness is questionable. Several
evaluations of the Humphrey field analyzer, which uses the Heijl-Krakau blind-spot-checking method,
revealed a high percentage of tests that were considered unreliable because the patient exceeded the
established criteria for fixation losses (190, 191 and 192). Suggestions for modifying reliability indices
to reduce testing time have included estimating short-term fluctuation from grids of single threshold
determinations; using intermittent monitoring for patients who perform well during the first 1.5 minutes
of testing; and substituting all indices with a new reliability parameter, which analyzes the inconsistency
of responses to the standard thresholding algorithm (193, 194 and 195).
As discussed earlier, there is a certain degree of short-term fluctuation in the retinal threshold sensitivity
profile (or hill of vision) among healthy individuals, especially in the midperiphery and superior
quadrant (196, 197 and 198). In addition, each person with normal vision shows some variation from
test to test, which is referred to as long-term fluctuation (198). However, both of these normal variations
are more likely in glaucomatous visual fields and must be taken into account when attempting to
interpret the significance of visual field data. Average total long-term fluctuation in patients with
clinically stable glaucoma is similar to that in healthy persons (199). However, long-term fluctuation can
be considerable in field areas with moderate loss of sensitivity (200). In addition, short-term fluctuation
is increased around both physiologic and glaucomatous scotomas (19, 201, 202). Short- and longterm
fluctuations are increased among older patients (203), and short-term fluctuation is often greatest in the
patient's first automated field test, indicating the influence of experience (204). In one study, a change in
mean sensitivity of approximately 5 to 7 dB between two successive fields was needed to have 95%
confidence that the trend would be confirmed by the third field (205).
Printouts and Automated Analyses
In addition to providing indications of patient reliability, as noted above, the computer printout records
the threshold for each retinal point tested along with various analyses of these measurements. The
clinician can read computerized visual field printouts by looking primarily for NFL defects, such as
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paracentral and arcuate scotomas and nasal steps, in the grayscale, numerical values, or symbols
representing a decibel range (Fig. 5.15). The Humphrey field analyzer also provides printouts in total
deviation (Fig. 5.15A), which is the difference between the measured threshold for each retinal point
tested and the age-corrected normal, and in pattern deviation (Fig. 5.15B), which is created from the
total deviation by adjusting it an amount equal to an average of the 17 worst test points. This helps
eliminate “background noise,” such as the generalized depression of a cataract. Both total and pattern
deviations are displayed in numeric and probability plots. Graphic methods have been devised to show
the development of visual field defects by analyzing recorded visual fields and displaying changing
areas as stripes (206), or triangles, or colored display of pointwise analysis, as in newer Progressor
software (discussed later).
Global Indices
Static threshold data can be analyzed mathematically, allowing detection of more subtle visual field
abnormalities. The statistical techniques used in this approach are referred to as visual field global
indices (Fig. 5.15C). An average of all points
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in the total deviation is referred to as mean deviation. These indices primarily reflect diffuse changes.
One way to detect localized defects is to calculate the number of threshold values that deviate
significantly from the age-corrected normal, which is called pattern standard deviation. Corrected
pattern standard deviation takes into account the short-term fluctuations.
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Figure 5.15 Computer printout of visual field of a right eye, measured by automated static technique,
showing superior arcuate scotoma and nasal step. A: Total deviation. B: Pattern deviation. C: Global
indices. D: Glaucoma hemifield test.
Short-Term Fluctuations
The visibility of the stimulus in standard static perimetry is typically adjusted by changing its intensity.
Although in the laboratory threshold sensitivity is considered to be the stimulus intensity at which the
patient responds 50% of the time, it is impractical to measure threshold so precisely in the clinical
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situation. Standard static threshold perimetry estimates the threshold sensitivity with approximately 2 dB
of precision by presenting the stimuli in increments to a certain location in the retina and recording the
value of the weakest stimulus seen. In some protocols, this process is repeated in random locations. The
difference between the patient's responses at the same location during the same session may be used to
calculate the standard deviation of the threshold values, called the shortterm fluctuation or intratest
variability.
Long-Term Fluctuation
The difference in threshold values in the same location between separate sessions is called the long-term
fluctuation. This typically represents physiologic rather than glaucomatous changes in visual function
over time. Although long-term fluctuation is not quantified in routine clinical perimetry, it should be
considered in interpretation of a series of visual fields.
Discrete scotomas may be preceded by variable threshold responses to repeated testing in the same area
(17, 207, 208). This fluctuation has also been referred to as scatter (209), or
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localized minor disturbances. Studies show that patients with glaucoma have substantially greater shortterm fluctuation, and to a lesser degree, long-term fluctuation (145, 210, 211). Although scatter is not a
definitive sign of glaucomatous visual field damage, it should be looked on with suspicion as an early
warning sign of impending absolute field loss.
Cluster Analysis
The global indices for localized loss are insensitive to the location of the defects. For example, three
abnormal locations could either be randomly distributed or clustered. Attempts to improve the
interpretation of data have led to the strategy of cluster analysis, or spatial correction. With this strategy,
contiguous clusters of test locations, which have an increased probability of appearing together in
typical glaucomatous field loss, are considered together in evaluating the visual field. They can be used
in calculating local indices, which should be more sensitive than global indices are, and may help to
dampen long-term fluctuation. In several studies, by using different cluster patterns, they have provided
an enhanced probability of distinguishing normal from glaucomatous fields, as well as a stable glaucoma
field from one that is deteriorating (212, 213, 214 and 215).
Glaucoma Hemifield Test
Another strategy to analyze the result of the visual field test is to compare sums of threshold values in
corresponding areas of the superior and inferior hemispheres (216, 217 and 218). In the Humphrey field
analyzer Statpac (discussed later), this is called the glaucoma hemifield test (GHT) (Fig. 5.15D). The
GHT performs analysis in five corresponding pairs of sectors that are based on the normal anatomy of
the retinal NFL. It then looks at the distribution of changes in pattern deviation and analyzes the
difference between upper and lower hemifields. It uses a large normal database to calculate the
significance of differences between the two hemispheres and has been shown to significantly improve
the ability to separate between normal and glaucoma fields (216, 219). It has good sensitivity and
specificity, although reproducibility is such that the use of two tests is recommended to improve
specificity (220, 221). This method allows a simple but clinically useful analysis of visual field changes
in patients with glaucoma. The GHT provides five plain language messages about the results of the
visual field test: within normal limits, outside normal limits, borderline, general reduction of sensitivity,
and abnormally high sensitivity (216). One study evaluated the repeatability of the GHT and found that,
although it was generally good on consecutive testing, there was enough disagreement to justify the use
of a second test for improved specificity in a clinical trial setting (221). The GHT “outside normal
limits,” used together with the pattern deviation probability plot, has been shown to provide high
sensitivity and specificity for detecting early glaucomatous visual field changes (222).
AGIS and CIGTS Scores
The Advanced Glaucoma Intervention Study (AGIS) investigators have developed a method of
interpreting visual field results on the basis of the number and depth of clusters of adjacent depressed
test sites in the upper and lower hemifields and in the nasal area of the total deviation plot, using the 24-
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2 threshold program of the Humphrey visual field analyzer (223). The Collaborative Initial Glaucoma
Treatment Study (CIGTS) investigators used a similar scoring system with a modification to evaluate
progression in patients with newly diagnosed glaucoma (224). Both AGIS and CIGTS scores range from
0 (no defect) to 20 (end-stage). Progression is defined as worsening of the score by 4 points in the AGIS
system and by 3 points in the CIGTS system.
Trend Analysis
Statistical models are available with some automated perimeters to help the clinician determine the
significance of visual field indices and variability. Those that have received several investigations are
the Delta program with the Octopus perimeter (225) and the Statpac with the Humphrey field analyzer
(226). With both systems, databases are used to calculate the probability of a measured value appearing
in a given age-defined population. In the case of the Humphrey field analyzer, the Statpac uses a large
normal database, and Statpac II uses a database of stable glaucoma patients. The Statpac printout
includes the reliability and global indices, the GHT, and probability maps, which display the field results
in terms of the frequency with which the measured findings are seen in the defined population (227,
228). The Statpac II also includes linear regression analysis and glaucoma change probability.
The glaucoma progression analysis (GPA) (Fig. 5.16) replaces the glaucoma change probability that is
used for fullthreshold testing. The GPA defines progression as more than three test points in the same
location on three consecutive tests.
A third statistical algorithm with the Humphrey field analyzer is the Progressor program for analysis of
serial fields, which is downloaded to a personal computer (229). The Progressor uses the data from all
visual fields in the series of examinations to perform pointwise linear regression analysis and to generate
a color-coded graphic display for simultaneous interpretation of the spatial and temporal changes (230).
Although most statistical models provide better agreement than experienced clinical observers do
regarding significant change over time, there is currently no generally accepted technique (231). One
study, which compared the results of a threshold program on the Octopus perimeter to those from
manual perimetry, demonstrated that indices used currently may not be clinically reliable in the
assessment of changes in the visual field (232). A study evaluating the three commercially available
computed statistical algorithms with serial Humphrey fields showed a high degree of variability among
the three, with none correlating well with the clinical impression (229). A study comparing the Statpac II
and Progressor showed that these two algorithms detected progression in the same patients, but
Progressor detected progression earlier than Statpac II did (233). Until improved statistical algorithms
are available, therefore, these data must be used with caution, and physicians should still rely primarily
on their own clinical judgment.
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Figure 5.16 Example of the GPA, which plots the mean deviation of sequential visual fields over time.
Reversibility of Glaucomatous Field Defects
Although visual field loss from glaucoma has traditionally been thought to be irreversible, central visual
acuity and the field of vision may improve if the IOP is reduced in the early stages of the disease (234,
235, 236 and 237). Visual field global indices with automated perimetry improved proportional to the
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amount of IOP reduction in two studies (238, 239). Other investigators, however, could not demonstrate
reversibility after pressure reduction was achieved by argon-laser trabeculoplasty (240, 241). These
conflicting findings may indicate that a critical level of pressure reduction or intervention at a critical
time in the disease process is needed to reverse field loss. Also, the ability to document improvement in
visual fields after surgical reduction of IOP may be enhanced by focusing on subgroups of test points
with lower baseline sensitivity (242).
Recording and Scoring Manual Visual Field Data
The complex nature of visual field data makes it difficult to reduce the information to simple
descriptions or numbers. Therefore, storage of the data in its raw form—that is, as transferred directly
from the testing screen—is usually the most practical means of record keeping. However, methods for
conversion of visual fields from kinetic and static perimeter charts to computer use, for area
calculations, graphic display, and storage in the patient's database, have been described (243, 244).
Visual Impairment and Disability Assessment
When it is necessary to estimate the percentage of functional visual field loss, a system is available (the
Esterman grids) in which the field is divided into 100 blocks of varying size
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according to functional value, with each representing 1% (245, 246 and 247). The system has been
adopted by the American Medical Association as a standard for rating visual field disability (248). Grids
are available for scoring the tangent screen, perimeter, or the binocular field (245, 246 and 247). In
patients with severe visual loss from glaucoma, the binocular Esterman score of data generated by an
automated perimeter correlated well with combined monocular visual field results (249).
Other Types of Perimetry
Glaucoma affects various components of the visual field, and subtle loss of central and peripheral vision
can be demonstrated in some patients with glaucoma before visual field changes are detectable with
standard techniques. Achromatic stimuli, used in standard automated perimetry, nonselectively stimulate
ganglion cells involved in the magnocellular and parvocellular pathways, and therefore are not always
sensitive enough to detect early glaucomatous damage. New strategies that are specifically designed to
test subgroups of ganglion cells (250, 251) are discussed next.
Short-Wavelength Automated Perimetry
Compared with white-on-white targets, color stimuli may influence the visual field results in one of two
ways. Color targets typically have less luminance and a lower stimulus value than white targets do.
More significantly, if the luminance is kept constant and the color saturation is varied, the stimulus value
might be more sensitive to specific color vision defects, as in some patients with glaucoma (252). Early
studies suggested that such a technique could reveal field defects that are larger than those obtained with
conventional white-on-white perimetry (253, 254), whereas other studies found color targets to be no
more sensitive than white ones in detecting glaucomatous defects (255, 256 and 257). These conflicting
results may be related to the colors selected for the test. Continued study has led to the following
observations with new test objects.
Testing one subgroup of small ganglion cells, called bistratified blue-yellow ganglion cells, that are
sensitive to blue stimuli may detect loss of visual function at much earlier stage of glaucoma than with
standard automated perimetry (258). Shortwavelength automated perimetry (SWAP) takes advantage of
this glaucoma-induced color vision deficit by presenting standard Goldmann size V, short-wavelength
blue targets on a bright yellow background (259, 260). Studies indicate that SWAP deficits represent
early glaucomatous damage and that the test may indicate significant change in visual function before it
is apparent on standard white-on-white visual fields (261, 262, 263, 264 and 265). Longitudinal studies
have demonstrated the ability of blue-on-yellow perimetry to predict the development of glaucoma in
patients with ocular hypertension, and in which patients early glaucomatous visual field loss is most
likely to progress (266, 267 and 268). Other studies have demonstrated a significant relationship
between structural optic nerve damage and SWAP visual field defects (263, 269). However, the test is
influenced by age and cataracts, and stringent statistical analysis in interpreting the results is necessary
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(270, 271, 272 and 273), but SWAP testing is unaffected by blue-blocking acrylic intraocular lens
implants, compared with clear acrylic implants (274). One study investigated whether SWAP, using a
screening program, can detect early glaucomatous damage before standard screening perimetric tests
can, and found that the SWAP screening program is more advantageous than conventional tests in
detecting early glaucomatous visual field defects (275). However, some patients with ocular
hypertension and early glaucomatous structural abnormalities may have normal blue-yellow perimetry
(276). The SWAP is available on the newer Humphrey field analyzer II. A new generation of SWAP
techniques uses more efficient strategies, such as SITA. By using this approach, testing time has been
reduced from 12 minutes to less than 4 minutes (277). SITA SWAP testing detects higher sensitivities
than fullthreshold SWAP does, and is equal to full-threshold SWAP in its ability to detect visual field
abnormalities (278, 279). The topography of the SWAP field is steeper than achromatic automated
visual fields (280). SWAP testing is also subject to greater long-term fluctuation and more learning
effect artifact, compared with achromatic automated visual fields. Thus, defects found by using this
method should be interpreted cautiously, and confirmation with a repeated SWAP test is advisable (281,
282).
Frequency Doubling Technology
Frequency doubling technology (FDT) perimetry is based on the frequency doubling illusion (283).
Each test stimulus is a series of white and black bands flickering at 25 Hz (284). FDT perimetry is
thought to be mediated by a subset of the largediameter ganglion cells, called the My ganglion cells, that
project to the magnocellular visual pathway (285). These cells are sensitive to motion and contrast and
are thought to be more vulnerable to glaucomatous damage (85, 286), although this view has been
questioned by some authors (287, 288, 289 and 290). The FDT is a portable (Fig. 5.17) and relatively
inexpensive tool with a short testing time (250, 291), qualities that make it a useful screening device
(250, 291, 292, 293 and 294). When administered in a suprathreshold screening mode, FDT perimetry
can be performed on a healthy eye in less than 90 seconds (284), and provide a higher detection rate for
early glaucoma than with SAP (295). (A comparison of FDT and SAP readouts is shown in Fig. 5.18.)
FDT showed greater than 96% sensitivity and specificity for detection of moderate and advanced
glaucoma, and greater than 85% for early glaucoma, when compared with SAP in a prospective study
(296). Because of its relatively quick acquisition times and high sensitivity, FDT is also advocated for
use in children. Children older than 14 years have the same normal threshold limits as adults do; for
children younger than 14 years, the mean deviations for normal decreased with decreasing age, with a
linear best fit of mean deviation of - 11 ± 1 dB for age down to 6 years (297). However, FDT perimetry
was reported to be less sensitive to visual field
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damage associated with neurologic disorders, compared with SAP (298). Sensitivity to FDT was found
to be reduced in the second tested eye if an opaque occluder was used, because of delayed postocclusion
light adaptation; a translucent occluder eliminated this reduction in sensitivity in the second eye (299).
The original FDT perimeter tested a maximum of 19 points over the central 20 (C-20) or 30 (N-30)
degrees of the visual field with both screening and threshold strategies (300) (Fig. 5.18). A secondgeneration FDT (Humphrey Matrix, 2003) uses smaller stimuli to examine a larger number of test
points, which may allow better early detection of glaucoma (300, 301 and 302) and has the following
testing strategies available: macula, 10-2; N30-F, 24-2, and 30-2. The GHT algorithm is available for the
24-2 and 30-2 testing strategies. FDT tests are also subject to learning and long-term fluctuation
artifacts; thus, abnormal test results should be interpreted cautiously, and confirmation with a repeated
test is advisable (303, 304 and 305).
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Figure 5.17 Frequency doubling technology perimeter.
Figure 5.18 Pattern deviation plots for SAP-SITA, FDT N-30, and FDT 24-2. Each plot shows the
locations tested and the results expressed as a grayscale pattern (denser patterns indicate deeper defects).
Probabilities are shown in the corresponding keys. (Reprinted from Racette L, Medeiros FA, Zangwill
LM, et al., Diagnostic accuracy of the Matrix 24-2 and original N-30 frequency-doubling technology
tests compared with standard automated perimetry. Invest Ophthalmol Vis Sci. 2008;49:954-960, with
permission.)
Contrast and Motion Sensitivity
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As noted above, the eye with glaucomatous damage appears to have reduced ability to perceive motion
and contrast, both centrally and peripherally (300, 307, 308). This may be related to preferential damage
to larger retinal ganglion cells, and motion and contrast perception tests may prove useful in the
detection of early glaucoma (306, 307 and 308). The detection of vernier offsets is also affected in
glaucoma, but it is not sensitive enough to distinguish patients with glaucoma from controls (309).
Various perimetric tests measure contrast and motion sensitivity in glaucoma, including gratings tests
for contrast sensitivity, vernier acuity, flickering stimuli, high-pass resolution perimetry, and random
motion automated perimetry (309, 310, 311, 312, 313, 314 and 315). (The application of these visual
function tests in glaucoma is discussed in Chapter 6.)
High-Pass Resolution Perimetry
High-pass resolution perimetry, or ring perimetry, is presumed to selectively test the parvocellular
system (314). The stimuli used in this test are rings of different size projected at different locations on
the computer screen. The rings have dark borders and bright centers, creating average luminance of the
stimulus equal to the luminance of the background. By also using high-pass spatial filtering, the targets
can be detected and resolved at the same ring size, in an effect known as vanishing optotype, allowing
rapid definition of the resolution threshold. The results of the test are presumed to correspond to the
density of ganglion cells; this test is therefore essentially a peripheral visual acuity test (250). Healthy
persons showed increased resolution threshold toward the periphery, a slight but significant decline in
sensitivity with age, and high repeatability (316), as well as reliability indices comparable to SAP (317).
Patients with glaucoma showed a significant reduction in overall resolution threshold (318), and the
results were comparable to standard perimetry in sensitivity and specificity (319, 320). Study findings
suggest that high-pass resolution perimetry could identify
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glaucomatous visual field damage in early and moderate stages of the disease (321, 322).
Random Dot Motion Automated Perimetry
Yet another technique, random dot motion automated perimetry, takes advantage of reduced motion
sense in patients with glaucoma by presenting a shift in position of dots in a defined circular area against
a background of fixed dots (306, 323). The patient should tell the direction (up, down, left, right) in
which the dots are moving. A preliminary study showed that patients with COAG manifest abnormal
motion perception with the test, compared with healthy persons (315). Patients with glaucoma have
demonstrated prolonged reaction time to the stimulus and less precise location of the stimuli (324). The
test takes approximately 15 minutes to perform (250). Localized visual field loss detected by motion
automated perimetry appeared to correspond to focal changes in optic disc topography, similar to those
found by SWAP and SAP (325).
Combining results of functional tests with structural tests may identify different elements of
glaucomatous damage and improve sensitivity and specificity of the tests (326).
Manual Perimetry
Although automated perimeters are being used with increasing frequency in clinical practice, the older,
manual perimeters may still provide valuable information, especially when a skilled observer performs
the test.
Tangent Screens
The tangent screen is a flat square of black felt or flannel with a central white fixation target on which
30 degrees of the vi sual field can be studied, The test is performed in mesopic lighting of approximately
7 foot-candles with the patient seated 1 or 2 m from the screen. Both kinetic and supra-threshold static
techniques can be used with the tangent screen. With the kinetic approach, the examiner moves a test
object from the periphery toward fixation until the patient indicates recognition of the target. The
procedure is repeated at various intervals around fixation until the isopter has been mapped. The
stimulus value of the test objects can be changed by varying the size and color. The corresponding
isopter is designated by the ratio of target diameter to the distance between patient and target, with both
expressed in millimeters, for example, “2/1000 white” for a 2-mm white test object at 1 m (when the
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color is not indicated it is understood to be white).
Figure 5.19 Goldmann manual perimeter. A: Patient's side, showing headrest (H), fixation target (F), and
projection device for test objects (P). B: Operator's side, showing telescope for fixation monitoring (T)
and visual field chart (C) for locating and recording position of test objects.
Suprathreshold static perimetry can be performed by turning the disc-shaped test object from the black
to the white side or by using a self-illuminating target with an on-off switch. Specific locations at which
the patient fails to see the target are then evaluated further with kinetic techniques.
The tangent screen has the advantages of low cost and simplicity of operation. However, reproducibility
of the fields, which is essential in managing patients with glaucoma, is limited by variations in
background lighting and stimulus value of the targets, and by difficulty in monitoring fixation.
Furthermore, it does not include the peripheral field, where early glaucomatous defects may appear.
Arc and Bowl Perimeters
With these instruments, both the central and peripheral fields of vision can be examined. The screen of
the perimeter may be a curved ribbon of metal (arc perimeter) or bowl shaped. The latter is preferable
for glaucoma examinations, and the prototype is the Goldmann perimeter (Fig. 5.19) (327). Other
similar instruments have been compared with the Goldmann unit,
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with variable results (328). The bowl of the Goldmann perimeter has a radius of 300 mm and extends
95% to each side of fixation. The target is projected onto the bowl, and the stimulus value of the test
object can be varied by changing the size or the intensity. Arbitrary designations for each value variable
are usually printed on the visual field chart, with O-V for size, and 1-4 for intensity. An isopter,
therefore, might be designated as “I2e,” which indicates a test object size of 0.25 mm2 and an intensity
of 10 millilamberts. The examiner can monitor the patient's fixation through a telescope in the center of
the bowl. The Goldmann perimeter can be used for both kinetic and static visual field testing. The
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Tübingen perimeter has been designed exclusively for the measurement of static threshold (profile)
fields and consists of a bowl-type screen and stationary test objects with variable light intensity (329,
330).
Figure 5.20 In-depth technique with Goldmann-type perimeter in which the visual field has been plotted
with five targets. The size and stimulus of the corresponding isopters are shown in the table in the lower
right of the figure. This demonstrates a normal visual field.
Specific Techniques for Manual Perimetry
In the context of glaucoma detection and management, manual kinetic visual field testing has two basic
aspects: (a) screening techniques to detect the presence of glaucomatous field loss, and (b) in-depth
techniques to more accurately determine the extent of the damage and to follow the fields for evidence
of progressive change.
Screening Techniques
Armaly developed a method of visual field screening for glaucoma that was modified by Drance and
associates and is commonly referred to as selective perimetry, or the Armaly-Drance technique (331,
332, 333 and 334). The basic concept is to test those areas in the visual field that have the highest
probability of showing glaucomatous defects. The technique uses Goldmann-type perimeter with
suprathreshold static perimetry to test for central field defects and both suprathreshold static and kinetic
perimetry to examine the peripheral field, with emphasis on the nasal and temporal periphery. This
technique revealed a high sensitivity and specificity, which made it suitable for clinical and survey
screening (332, 334). An additional modification is to use the V4e isopter nasally to rule out crowding
of the peripheral nasal isopters (45).
Another technique for use with Goldmann-type perimeters uses three suprathreshold targets in three
concentric zones from fixation in accordance with the normal physiologic sensitivity gradient (335).
Other investigators have developed protocols to significantly reduce the number of test points without
sacrificing sensitivity or specificity by concentrating the testing in those portions of the field where a
defect is most likely to be found (336, 337).
In-Depth Techniques
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When a glaucomatous field defect is suspected by use of a screening technique, the physician has two
choices. The patient can be asked to return another day for a repeated screening field or an in-depth
study. In many cases, however, it is more practical to proceed with the in-depth test at the time the
defect is detected. The principle of in-depth field testing is to map out the size and shape of all scotomas
and complete isopters by using the central threshold target and two or more additional targets of greater
stimulus value (Fig. 5.20). However, automated static perimetry has certainly more value in studying
areas of known loss for the depth and shape of the scotoma and for subtle evidence of progressive
damage in serial fields.
KEY POINTS
The normal visual field may be depicted as a three-dimensional contour, representing areas of
relative retinal sensitivity and characterized by a peak at the point of fixation, an absolute
depression corresponding to the optic nerve head (blind spot), and a sloping of the remaining areas
to the boundaries of the field.
Early glaucomatous damage may produce a generalized depression of this contour, which can be
demonstrated with several psychophysical tests.
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The more specific visual field changes of glaucoma, however, are localized defects that
correspond to loss of retinal nerve fiber bundles, and include paracentral and arcuate scotomas
above and below fixation and steplike defects along the nasal midline (nasal step).
Instruments used to measure the field of vision (perimeters) may have static or kinetic targets,
which can be controlled automatically or manually. The targets are presented against a
background that is bowl shaped or flat (tangent screen), with the former units providing more
reliable measurements.
Comparative studies indicate that automated static perimeters, particularly those using new
enhanced testing algorithms, are more sensitive than manual perimeters are at detecting and
following glaucomatous visual field loss.
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6 - Glaucomatous Influence on Visual Function
> Table of Contents > SECTION I - The Basic Aspects of Glaucoma > 6 - Glaucomatous Influence on
Visual Function
6
Glaucomatous Influence on Visual Function
In addition to the previously discussed visual field changes in glaucoma (see Chapter 5), other visual
function tests may have abnormal results early in glaucoma. Some of these tests may one day prove
useful in detecting the presence and progression of glaucoma and in judging the efficacy of glaucoma
therapy.
BRIGHTNESS SENSITIVITY
Patients with glaucomatous optic atrophy have decreased light sensitivity when dark adapted, which
correlates with the degree of nerve damage (1), and dark adaptation, tested with chromatic stimuli, has
been reported to be abnormal in patients with ocular hypertension (2). The results of some studies
provided little evidence for photoreceptor abnormalities in glaucoma (3, 4), but other studies suggested
that the photoreceptors may be involved in glaucomatous damage (5, 6). Light sensitivity can also be
evaluated with a brightness ratio test, in which the patient discriminates the difference in sensitivity of
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the two eyes to light, and it has been suggested that tests of this type may be useful in glaucoma
screening (7, 8). In preliminary studies, patients with open-angle glaucoma had abnormal responses on
dichoptic testing, in which one half of a test object is presented to one eye, and the other half to the
fellow eye, to help determine the location of a defect in the visual pathway (9).
COLOR VISION
Reduced sensitivity to colors has been described in patients with ocular hypertension, tilted discs, and
various forms of glaucoma, and may precede any detectable loss of peripheral or central vision by
standard acuity or visual field testing (10). Compared with achromatic sensitivity, color sensitivity was
found to be more affected in glaucoma (11). Most studies agree that the color vision deficit is associated
primarily with blue-sensitive pathways (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25). This is
consistent with the observation that blue signals are detected by the short-wavelength cones, and then
processed by the blue-yellow bistratified ganglion cells, which are different from the midget ganglion
cells (26, 27). These cells project their axons to the interlaminar koniocellular layers of the lateral
geniculate nucleus (28). Blue cones contribute little to the sensation of brightness or to visual acuity,
which may account for why standard visual
acuity tests, perimetry, or contrast sensitivity studies might miss an associated visual deficit. The color
visual dysfunction is strongly related to elevated intraocular pressure (IOP) levels (22, 23), suggesting
that the damage is pressure induced. Selective loss of red-green sensitivity has been observed in some
patients with glaucoma (29). However, chromatic visualevoked potential (VEP), which utilizes redgreen flicker, was found to be altered in nonglaucomatous optic neuropathies, but not glaucoma (30).
It is unclear whether the loss of color vision and the visual field changes associated with nerve fiber
bundle loss share the same mechanism. Ocular hypertensive eyes with yellow-blue and blue-green
defects were found to have diffuse early changes in visual field sensitivity (17) and an increased risk of
glaucomatous visual field loss, compared with similar eyes that did not have these color vision
disturbances (14). The same color abnormalities in patients with early glaucoma correlated significantly
with diffuse retinal nerve fiber loss (24). However, no significant correlation between color vision scores
and visual field performance was found among patients with ocular hypertension when age correction
was applied to the color variable (31), and another study revealed no clear association between early
glaucomatous cupping and color vision anomalies (18). Specificity is limited by the fact that the tritan
deficit is also the one most frequently seen with age-related changes. When study populations were
matched for age and lens density, however, color vision loss in glaucoma was still attributable in part to
the disease process (21).
In most reported studies, the color vision testing was performed with the Farnsworth-Munsell 100-hue
test, dichotomous (D-15) tests, or variants of these, all of which are laborious and of questionable
precision. One study has shown that halogen lighting is preferable for the Farnsworth-Munsell 100-hue
test in glaucoma and confirmed the presence of blue-yellow pathway deficiency in glaucoma (32).
Another study has shown that although the error scores on the Farnsworth-Munsell 100-hue test were
elevated in glaucomatous eyes, the test did not always discriminate well and seemed to lack a high
diagnostic value (33).
Various tests have been devised to overcome limitations of the Farnsworth-Munsell test, including
computer-driven monitors that present flickering color contrasts or peripheral color contrasts, an
automatic anomaloscope, a color contrast sensitivity test in which the target and surround have the same
luminance but different chromaticity, and a personal computer (34, 35, 36, 37 and 38). Even with the
most sensitive, precise system, however,
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glaucoma is not always detected, suggesting that some patients with glaucoma have true preservation of
color vision (37, 39, 40).
As discussed in Chapter 5, short-wavelength automated perimetry (SWAP), which projects a blue target
on a yellow background, has been shown to detect glaucoma damage earlier than conventional white-onwhite perimetry (41, 42, 43 and 44). SWAP has also been found to be more sensitive to progression of
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visual field loss and to progression of glaucomatous disc cupping (45, 46).
Contrast Sensitivity
Subtle loss of both central and peripheral vision can be demonstrated in some patients with glaucoma,
before visual field changes are detectable with standard techniques, by measuring the amount of contrast
required for a patient to discriminate between adjacent visual stimuli (47, 48, 49, 50, 51 and 52). In
some studies, the contrast sensitivity impairment correlates with visual field (48, 49 and 50, 53),
especially with the central visual field and optic nerve head (50, 54) damage. The yield of detecting
glaucoma may be increased by measuring peripheral contrast sensitivity, 20 to 25 degrees eccentrically
(55, 56). Tests to measure contrast sensitivity may use spatial or temporal strategies. Although spatial
contrast sensitivity may be a useful adjunct, caution has been advised in interpreting the results without
considering additional clinical data (52). The overlap with other causes of reduced spatial contrast
sensitivity, including age, creates high false-negative and false-positive rates (50, 51, 57, 58). Spatial
contrast sensitivity has been shown to decrease in persons with healthy eyes after 50 years of age, which
appears to be independent of the crystalline lens (59, 60). Although spatial summation properties differ
between M- and P-mediated pathways, the underlying spatial summation properties associated with
these pathways are similar in control patients and those with glaucoma (61). In a study comparing the
decrease in contrast sensitivity between normal aging and glaucoma, aging decreased low-spatial
frequencysensitive components of both the M and P pathways. Glaucoma results in a further reduction
of sensitivity that does not seem to be selective for M or P functions, which the investigators presumed
were mediated by cells with larger receptive fields (62). For reference, frequency doubling technology
(FDT) measures the contrast threshold to low spatial frequency, high temporal frequency sinusoidal
luminance profile bars (63).
Sine-wave gratings of parallel light and dark bands (Arden gratings), in which the patient must detect
the striped pattern at various levels of contrast and spatial frequencies, have been evaluated extensively
in this group of psychophysical tests (47). The original Arden gratings were limited by the subjectivity
of the required responses (64, 65). A modification, in which the patient must indicate the orientation of
the gratings, has been reported to minimize this limitation (65). The testing methods include computercontrolled video displays and photographically reproduced grating patterns, both of which have given
good approximations of the spatial contrast sensitivity function (66). One of these tests uses sine-wave
gratings of low spatial frequency and laser interference fringes to increase sensitivity to peripheral
defects (67, 68 and 69).
Performing these techniques, including sinusoidal grating targets, is difficult and time consuming. An
effort to minimize these limitations has led to the development of high-pass resolution perimetry
(discussed in Chapter 5).
Temporal contrast sensitivity, in which the patient must detect a visual stimulus flickering at various
frequencies, provides another measure of contrast sensitivity and appears to be more useful than spatial
contrast sensitivity in patients with glaucoma. The stimulus may be presented as a homogeneous
flickering field (flicker fusion frequency) or as a counterphase flickering grating of low spatial
frequency (spatiotemporal contrast sensitivity) (59, 70, 71). Patients with glaucoma may have reduced
function with either method, although the latter appears to be a more sensitive test (71, 72).
Spatiotemporal contrast sensitivity was also found to be more useful in detecting glaucoma than spatial
contrast sensitivity testing of the central retina was, although, again, the usefulness of the test is limited
to those younger than 50 years (59). Other studies have found age to be a less significant factor in
sensitivity loss, although one study suggested that cardiovascular disease may be associated with foveal
dysfunction (73, 74 and 75). There is also a question as to whether temporal contrast sensitivity loss
among patients with ocular hypertension represents early glaucomatous damage or a transient effect of
raised IOP. One study suggested that either mechanism may be found within subsets of this population
(76). Reducing the IOP in patients with glaucoma may improve contrast sensitivity at high frequencies
of 18 cycles/degree (77).
Several techniques have been evaluated to improve the usefulness of contrast sensitivity testing. One
study suggested that the determination of a ratio between spatial contrast sensitivity and flicker
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sensitivity measures visual pathology more precisely than the absolute value of either test does (78).
Another test of temporal contrast sensitivity, in which the patient must discriminate two rapidly
successive pulses of light from a single pulse, is reported to be highly sensitive and specific in
distinguishing glaucomatous eyes from healthy ones (79). Another test, the whole-field scotopic retinal
sensitivity test, uses a flashlight-sized device in which the patient views a white light in the entire visual
field and is asked to detect alternating illuminated and dark fields at 1-second intervals (80). This test
may be useful as a screening tool (80, 81), although one study found too much overlap between healthy
persons and individuals with ocular hypertension (82).
Another attempt to use a temporal contrast or flickering target has been called temporal modulation
perimetry or flicker perimetry (83, 84 and 85). In healthy eyes there is an age-related loss of temporal
modulation sensitivity (83). It appears to be less affected by visual acuity or retinal degradation than
either light-sense or resolution perimetry, and it is more sensitive than light-sense perimetry to
increasing IOP (84, 85 and 86).
Different target shapes and patterns, which the patient must distinguish, are also reported to be of
particular value
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in detecting optic nerve disease (87). In one study with pattern discrimination perimetry, long-term and
short-term fluctuations were clinically significant but did not prevent adequate separation between
normal and abnormal measurements (88). Visual function in glaucomatous eyes, as measured by
contrast sensitivity, has been shown to improve after (3-ßblocker therapy (89).
ELECTROPHYSIOLOGIC STUDIES
Most measures of visual fields and other visual functions are dependent on the patient's subjective
response. A significant amount of work is also being done on alternative, objective methods of
evaluating the visual field. The pattern electroretinogram, the photopic negative response of the
electroretinogram, and the multifocal VEP (mfVEP) appear to have the most potential to detect early
glaucomatous damage that may not be detected by standard automated perimetry (90, 91, 92, 93, 94, 95
and 96). Of the currently available electrophysiologic tests, the mfVEP is the only one that can provide
topographic information about the visual field defects. The relation between electrophysiologic tests and
the underlying damage to ganglion cells is still not completely understood, but it has been suggested that
the signal in the mfVEP response may be linearly related to the ganglion cells loss (93). Patients with
glaucoma were also found in one study to have increased baseline values with electro-oculography (97),
but a subsequent study did not confirm that finding (98).
Electroretinograms
Electroretinograms (ERGs) evoked by reversing checkerboard or grating patterns, referred to as pattern
ERGs (PERGs), are sensitive to retinal ganglion cell and optic nerve dysfunction and have reduced
amplitudes in patients with glaucoma (92, 99, 100, 101, 102, 103, 104, 105 and 106). PERG may detect
early damage to ganglion cells (91), which may explain why reduced PERG amplitudes appear in the
early stages of glaucoma and in some eyes with ocular hypertension, especially those at elevated risk for
glaucoma (101, 105, 106, 107, 108, 109 and 110). These findings suggest that PERG may be useful in
discriminating between those patients with ocular hypertension who will develop visual field loss and
those who will not.
Studies differ on whether PERG correlates with IOP and disc topography, with one study showing no
correlation and others showing an association with IOP control, computed optic nerve head analysis, or
the retinal nerve fiber layer thickness (108, 111, 112 and 113). The PERG has been shown to correlate
with visual field indices (114), and visual field defects are associated with PERG reduction in the
corresponding hemisphere (115). However, no precise correlation was found with color vision deficits
(116). Decreased amplitude and an increase in peak latency were found to correlate with increasing age
(104), paralleling the estimated normal loss of ganglion cells. Indeed, reduction in PERG was directly
related to histologically defined optic nerve damage in a monkey model (117). PERG in combination
with SWAP was shown in one study to improve the power to predict progression of visual field loss
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(118).
The ERG evoked by a flash of light (flash ERG) is affected more by outer retinal elements and is not
typically abnormal in glaucoma. Acute IOP elevation in cats, however, caused a reduction in both
pattern and flash ERG, proportional to the reduction in perfusion pressure and regardless of the absolute
IOP, suggesting a vascular mechanism to which the ganglion cells are less likely to recover (119).
Patients with glaucoma in one study had reduced ERG amplitudes in response to a flickering stimulus
(flicker ERG) (106). One study suggested that the flash and pattern ERG changes in glaucoma cannot be
attributed simply to optic atrophy, suggesting additional outer retinal damage in glaucoma (120).
Multifocal ERG (mfERG) (Fig. 6.1) permits simultaneous recording of multiple spatially localized ERG
(121, 122). It consists of the same components as a standard ERG (123). Preliminary studies suggest that
it does not appear to correlate well with glaucomatous damage and may be able to detect abnormalities
before automated achromatic visual fields can (124, 125, 126, 127, 128 and 129).
Visual-Evoked Potentials
VEPs may also be abnormal in patients with chronic or acute glaucoma, although this is more variable
than the PERG response (15, 99, 102, 103, 117, 130, 131, 132 and 133). However, larger diameter axons
of the magnocellular pathway, which may be preferentially damaged in glaucoma (134), correlate with
fast, transiently responding retinal ganglion cells, and a reduced response to high-frequency flicker VEP
(greater than 13 Hz) has been shown to correlate with the degree of glaucomatous damage (135, 136,
137 and 138). Blue-on-yellow VEP may be useful in glaucoma research and may be an objective
electrophysiologic test for monitoring patients with glaucoma (139, 140).
mfVEPs (Fig. 6.2) can be recorded simultaneously from many regions of the visual field and appear to
provide objective measures of glaucomatous damage (94, 141, 142, 143, 144 and 145). The amplitude
and waveform of the mfVEP responses vary across individual patients and within the visual field of an
individual. Methods for analyzing the responses and for displaying the results of mfVEP compare the
monocular responses from the two eyes of an individual and produce a map of the defects in the form of
a probability plot, similar to the one used to display visual field defects measured with standard
automated perimetry. It is hypothesized that both the signal in the mfVEP and the sensitivity of the
Humphrey visual field perimeter are linearly related to ganglion cell loss (94).
New approaches will allow a direct comparison of the efficacy of the mfVEP and standard automated
perimetry in detecting glaucomatous damage. For example, one study evaluated the reliability of VEPs,
obtained with chromatic and achromatic patterns in healthy persons and patients
P.124
with suspected glaucoma without subjective visual field defects, and found that patients with suspected
glaucoma had greater impairment of VEPs to blue-black checkerboards (146). The mfVEP may develop
a significant role in the clinical management of glaucoma (145), although it is unlikely to replace static
automated achromatic perimetry in the near future (142).
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Figure 6.1 The multifocal elec-troretinogram (mfERG) display. A, top: The mfERG display with circles
drawn to indicate radii of 5 degrees (thick, solid, dark gray), 15 degrees (thinner solid), and 25 degrees
(dashed light gray). A, middle: A schematic of the eye illustrates where the image of the display falls. A,
bottom: The three-dimensional mfERG density plot of the responses (E) from a normal subject. B: The
mfERG display at one moment in time. C: The stimulation sequence of two sectors in. D: The single
continuous ERG record generated by the display. E: The 103 mfERG responses (first-order kernel)
extracted by correlating the stimulus sequence (C) with the continuous ERG record (D). (From Hood
DC, Odel JG, Chen CS, et al. The multifocal electroretinogram. J Neuroophthalmol. 2003;23:225.)
Steady-state VEP may be able to detect glaucomatous loss earlier than automatic achromatic perimetry
can (63).
AFFERENT PUPILLARY DEFECT
A relative afferent pupillary defect offers yet another measure of visual pathway disturbance in
glaucoma (147). It has been shown to be proportional to the amount of visual field loss and may precede
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detectable field loss by static automated perimetry (148, 149 and 150). When pupillary status, such as
marked miosis, prevents determination of relative afferent pupillary defect, brightness comparison
testing has been shown to correctly predict the presence of a relative afferent pupillary defect in 92% of
patients with glaucoma (151). Pupillary evaluation by using pupillometry and testing relative sensitivity
between stimuli present in superior and inferior visual fields was able to correctly identify visual field
defects in 70% of patients with glaucoma (152).
KEY POINTS
Some patients with glaucoma may have abnormal responses to brightness and contrast sensitivity
(especially temporal) and color vision (especially blue sensitivity), although these findings are
insufficiently consistent to have clinical value at this time.
Objective measures of visual function, including ERG and VEP, may also be abnormal in
glaucoma patients and may one day provide useful clinical tools.
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Figure 6.2 A: The mfVEP display with 60 scaled sectors. B: The averaged mfVEP responses from the
right and left eyes of 30 control subjects for 60 sectors. The circles on the right have radii of 2.6 degrees
(inside), 9.8 degrees (middle), and 22.2 degrees (outside). C: The mfVEP display divided into 16
groups. Each group includes four sectors, except for the (center four groups, which include three sectors.
D: The averaged mfVEP responses from the 30 control subjects summed by the 16 groups shown in
panel C. E: The responses from panel B summed and averaged separately for the upper and lower field
and summed and averaged for the entire field. The calibration bars in panels B, D, and E indicate 200
nV and 100 ms. (Reprinted from Hood DC, Greenstein VC. Multifocal VEP and ganglion cell damage:
applications and limitations for the study of glaucoma. Prog Retin Eye Res. 2003;22:201-251, with
permission.)
P.126
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139. Korth M, Nguyen NX, Junemann A, et al. VEP test of the blue-sensitive pathway in glaucoma.
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7 - Classification of the Glaucomas
Page 1 of 425
Shields > SECTION II - The Clinical Forms of Glaucoma >
> Table of Contents > SECTION II - The Clinical Forms of Glaucoma > 7 - Classification of the
Glaucomas
7
Classification of the Glaucomas
APPROACHES TO CLASSIFICATION OF GLAUCOMA
There are several systems by which the glaucomas have been classified. The most commonly used ones
are based on (a) etiology—that is, the underlying disorder that leads to an alteration in aqueous humor
dynamics or retinal ganglion cell loss or (b) mechanism—that is, the specific alteration in the anterior
chamber angle that leads to a rise in intraocular pressure (IOP). One disadvantage of both systems is that
they incorrectly suggest that elevated IOP is the primary risk factor in the glaucomas. A second
disadvantage is that neither system incorporates the underlying genetic architecture that contributes to
the majority of glaucomas. However, until we understand the causes and mechanisms of the glaucomas
more completely, these systems provide the most useful ways to classify the glaucomas.
CLASSIFICATION BASED ON ETIOLOGY
The glaucomas have traditionally been divided on the basis of primary and secondary forms. This
division is arbitrary and artificial, however, in that all glaucomas are secondary to some abnormality,
whether inherited or environmental. The historical basis for this division was the assumption that the
initial events leading to outflow obstruction and IOP elevation in those glaucomas called primary (e.g.,
open-angle, angle-closure, and congenital) are confined to the anterior chamber angle or conventional
outflow pathway, with no apparent contribution from other ocular or systemic disorders. These
conditions typically are bilateral and probably have a genetic basis. In contrast, other glaucomas have
been classified as secondary because of a partial understanding of underlying, predisposing ocular or
systemic events. These latter glaucomas may be unilateral or bilateral, and some may have a genetic
basis, whereas others are acquired.
In reality, the concept of primary and secondary glaucomas largely reflects our incomplete
understanding of the pathophysiologic events that ultimately lead to glaucomatous optic atrophy and
visual field loss. As our knowledge of the mechanisms underlying the causes of the glaucomas continues
to expand, the primary and secondary classifications become increasingly artificial and inadequate.
Furthermore, glaucomas caused by developmental anomalies of the anterior chamber angle do not fit
neatly into either category. For these reasons, we recommend replacing traditional concepts with a new
scheme that provides a better working foundation for the concepts of mechanism, diagnosis, and therapy
that will shape the management of the glaucomas for the foreseeable future. This classification is used in
this text for the discussion of the various forms of glaucoma.
Stages of Glaucoma
Glaucomas can be considered to consist of five stages:
Stage 1—initiating events
Stage 2—structural alterations
Stage 3—functional alterations
Stage 4—retinal ganglion cell and optic nerve damage
Stage 5—visual loss
The initiating events (stage 1) include the condition or series of conditions that set in motion the chain of
events that may eventually lead to optic nerve damage and visual loss, but which precede any pathologic
or physiologic alterations related to aqueous humor dynamics or optic nerve function. Structural
alterations (stage 2) are those tissue changes that precede, but may eventually lead to, alterations of
file://C:\Documents and Settings\Sai\Local Settings\Temp\~hh5DBE.htm
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aqueous humor dynamics or optic nerve function. Functional alterations (stage 3) are those physiologic
abnormalities that may lead indirectly or directly to optic nerve damage. Optic nerve damage (stage 4)
represents the loss of retinal ganglion cells and their associated axons as a result of the events in stage 3,
which eventually leads to progressive loss of vision (stage 5). The first three stages can be further
subdivided into events that are pressure related and those that are pressure independent (Table 7.1).
In the pressure-related subdivision, the initiating events (stage 1) are the conditions that may lead to
structural alterations in the aqueous outflow system. In some glaucomas, this could be a genetic defect
with an associated protein abnormality; in other glaucomas, this may be due to acquired events, such as
trauma, inflammation, or a retinal vascular disorder, some of which may also have a genetic
predisposition or may be indirectly influenced by genetic disorders. The structural alterations (stage 2)
are tissue changes in the outflow system, which may lead to increased resistance to aqueous outflow and
subsequent elevation of the IOP. Such changes might be subtle alterations in the endothelial cells or
extracellular matrix of the trabecular meshwork or more obvious obstructive mechanisms, such as
membranes over the anterior chamber angle, scar tissue in the meshwork, intertrabecular debris, or
developmental anomalies. These changes can sometimes be detected by gonioscopy. The functional
alterations (stage 3) include obstruction to aqueous outflow that is sufficient to increase the IOP, which
(in pressure-related glaucoma mechanisms) may lead to the glaucomatous optic neuropathy (stage 4)
and eventually to progressive loss of visual field (stage 5). Another
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emerging possibility is that cerebrospinal fluid pressure may be abnormally low or high, thus affecting
the translamina cribrosa pressure gradient, weakening structural support to axons (as described in
Chapter 4).
Table 7.1 A Staging System for Glaucoma
Stage
Defining Aspect
Events
1. Initiating
The series of events that Pressure-related: genetic, acquired
events
may lead to stages 2-5
Pressure-independent: genetic, toxic, or acquired
susceptibility to apoptosis or ganglion cell death
2. Early structural Tissue changes
Pressure-related: alterations in aqueous outflow system
alterations
Pressure-independent: alterations related to ganglion cells
or optic nerve head (e.g., vascular, structural, or
physiologic)
3. Functional
Physiologic changes
Pressure-related: elevated IOP
alterations
Pressure-independent: reduced axonal conduction, vascular
perfusion, laminar deformity, others
4. Optic nerve
Retinal ganglion cell and Glaucomatous optic neuropathy and visual field loss
damage
axon loss
5. Visual loss
Progressive loss of visual Glaucomatous optic neuropathy and visual field loss
field
The specific events in the pressure-independent subdivision are not as well understood and are, in large
part, only speculative. The initiating events (stage 1) probably have a genetic basis, however, with
alterations in proteins that may lead to structural changes directly related to the ganglion cells or optic
nerve head. The structural alterations (stage 2) may be subtle tissue changes in blood vessels supplying
the optic nerve head or in supportive elements of the lamina cribrosa or, likely, in additional ways that
are not yet understood. The functional alterations (stage 3) may be reduced axonal conduction, vascular
perfusion to axons in the optic nerve head, or a progressive deformity of the lamina cribrosa that may
lead (alone or in conjunction with a relative IOP elevation) to glaucomatous optic neuropathy (stage 4)
and subsequent loss of visual field (stage 5).
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Although our knowledge of the first three stages that lead to optic nerve damage and our ability to detect
and treat these events are incomplete for most glaucomas, there are some glaucomas for which we have
not only a partial knowledge of the events in each stage but also treatments for early intervention at
stage 1. In neovascular glaucoma, for example, an initiating event (stage 1) may be a central retinal vein
occlusion, which can lead to release of vascular endothelial growth factor and other cytokines that may
lead to a structural alteration (stage 2) in the form of a fibrovascular membrane over the anterior
chamber angle, which may eventually cause a functional alteration (stage 3) by obstructing aqueous
outflow with a rise in IOP, which usually leads to optic nerve damage (stage 4) and eventual loss of
visual field (stage 5). An understanding of this sequence provides a rational basis for early intervention
with panretinal photocoagulation at stage 1 in selected patients. Such an approach to diagnosis and
management should be the ultimate goal for all forms of glaucoma. As the initial events for an
increasing number of the glaucomas become known, a complete classification scheme may eventually
be developed on the basis of these initial events. However, until continued research provides the answers
to these gaps in our knowledge, the etiologic classification scheme shown in Table 7.2 can be developed
only partially.
Chronic Open-Angle Glaucomas
This category of glaucomas constitutes at least half of all the glaucomas and has been referred to by
various names, including primary open-angle glaucoma, chronic open-angle glaucoma, and chronic
simple glaucoma. To de-emphasize use of the “primary” and “secondary” terminology in glaucoma, the
term chronic open-angle glaucoma is used in this text. A more appropriate term, however, might be
idiopathic open-angle glaucoma, because our failure to provide more precise terminology stems from
our lack of knowledge regarding the related mechanisms.
Although the initial events leading to chronic open-angle glaucoma are unknown, there is mounting
evidence that inherited susceptibilities lead to increased resistance to aqueous outflow and increased
vulnerability of the optic nerve head to a particular IOP level.
Pupillary Block Glaucoma
Among the so-called primary angle-closure glaucomas, the most common variation is pupillary block
glaucoma. The term pupillary block glaucoma is best reserved for situations with evidence of optic
nerve damage related to the angle-closure mechanism. A considerable amount of information is
available regarding the initial events and mechanisms of outflow obstruction in pupillary block
glaucoma. Therefore, there is no
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basis for distinguishing this condition—considered a primary glaucoma—from other disorders
previously classified as secondary glaucomas. Pupillary block glaucoma may be divided into acute and
subacute forms, although these forms merely represent different clinical manifestations, which can both
occur at different times in the same patient. A third form, called chronic angle-closure glaucoma, is
characterized by the presence of peripheral anterior synechiae. With a subset of chronic angle-closure
glaucomas called creeping angle-closure glaucoma, peripheral anterior synechiae slowly advance
forward circumferentially, making the iris insertion appear to become more and more anterior. With
another form called combined
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mechanism glaucoma, IOP elevation persists after peripheral iridotomy for the angle-closure
component, despite an open, normal-appearing anterior chamber angle. Some classification schemes
have included the plateau iris syndrome with primary angle-closure glaucomas, although recent studies
of the mechanism suggest that it might more appropriately be included with glaucomas associated with
disorders of the iris and ciliary body (1).
Table 7.2 Classification of the Glaucomas Based on Initial Events
A. Open-angle glaucomas without other known ocular or systemic disorders
1. Chronic open-angle glaucoma
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2. Normal-tension glaucoma
B. Angle-closure glaucomas without other known ocular or systemic disorders
1. Pupillary block glaucomas
2. Combined mechanism glaucoma
C. Developmental glaucomas
1. Congenital glaucoma
2. Juvenile open-angle glaucoma (overlap with chronic open-angle glaucoma)
3. Axenfeld-Rieger syndrome
4. Peters anomaly
5. Aniridia
6. Other developmental anomalies
D. Glaucomas associated with other ocular and systemic disorders
1. Glaucomas associated with disorders of the corneal endothelium
a. Iridocorneal endothelial syndrome
b. Posterior polymorphous dystrophy
c. Fuchs endothelial corneal dystrophy
2. Glaucomas associated with disorders of the iris and ciliary body
a. Pigmentary glaucoma
b. Iridoschisis
c. Plateau iris
d. Iris and ciliary body cysts
3. Glaucoma associated with disorders of the lens
a. Exfoliation syndrome
b. Glaucomas associated with cataracts
c. Glaucomas associated with lens dislocation
4. Glaucomas associated with disorders of the retina, choroid, and vitreous
a. Neovascular glaucoma
b. Glaucomas associated with retinal detachment and vitreoretinal abnormalities
5. Glaucomas associated with intraocular tumors
a. Malignant melanoma
b. Retinoblastoma
c. Metastatic carcinoma
d. Leukemias and lymphomas
e. Benign tumors
6. Glaucomas associated with elevated episcleral venous pressure
7. Glaucomas associated with inflammation
a. Glaucomas associated with uveitis
b. Glaucomas associated with keratitis, episcleritis, and scleritis
8. Steroid-induced glaucoma
9. Glaucomas associated with ocular trauma
10. Glaucomas associated with hemorrhage
11. Glaucomas after intraocular surgery
a. Ciliary block (malignant) glaucoma
b. Glaucomas in pseudophakia and aphakia
c. Epithelial, fibrous, and endothelial proliferation
d. Glaucomas associated with corneal surgery
e. Glaucomas associated with vitreoretinal surgery
Developmental Anomalies of the Anterior Chamber Angle
Numerous developmental disorders associated with anomalies of the anterior chamber angle can lead to
IOP elevation. The initial event is probably a genetic defect in most cases, although some cases may
stem from an acquired, intrauterine insult. The developmental anomaly may be a high insertion of the
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anterior uvea in the trabecular meshwork, incomplete development of the meshwork or Schlemm canal,
or broad iridocorneal adhesions. One group of developmental glaucomas was previously classified with
the primary glaucomas because it has no apparent consistent association with other ocular or systemic
anomalies. This group includes congenital, or infantile, glaucoma and juvenile open-angle glaucoma,
which differ primarily by the age of onset. Other conditions in this category have a wide range of
associated ocular and systemic developmental abnormalities. Additional developmental disorders, such
as those associated with the vitreous and retina, may lead to glaucoma, usually by an angle-closure
mechanism; in the present scheme, these disorders are classified as glaucomas associated with
abnormalities of a particular ocular structure (e.g., persistent hyperplastic primary vitreous).
Glaucomas Associated with Other Ocular Disorders
It is this large group of glaucomas that was previously classified as secondary glaucomas. In some cases,
the initial events involve an abnormality of a specific ocular structure, such as the corneal endothelium,
iris, ciliary body, lens, retina, choroid, or vitreous. In other cases, the initial events may involve a tumor,
inflammation, hemorrhage, or accidental or surgical trauma. Many of these initial events are influenced
by an inherited susceptibility, whereas others are acquired. Each of these broad categories of glaucoma
usually contains subdivisions, based on different series of events that eventually lead to outflow
obstruction.
A Note on Molecular Etiology
Now that several genes have been localized for various glaucomas, the hope of being able to reclassify
these disorders on the basis of molecular etiology is being realized (2). Although separating patients
with adult-onset chronic open-angle glaucoma on the basis of phenotype is difficult, the molecular
classification has already allowed us to recognize several genetic forms of glaucoma. Characterizing
additional genes and mutations will be extremely helpful in classifying disease in individual patients,
with a view to being able to provide tailored prognostic and therapeutic information (as discussed in
Chapter 8). Some glaucomas may be associated with more than one gene, such as the Axenfeld-Rieger
syndrome, which appears to be caused by at least three different genes located on chromosomes 4, 6,
and 13, once again underscoring genetic heterogeneity (3, 4, 5 and 6). Others are non-Mendelian or
complex, and probably involve more than one gene plus environmental factors. An example is
exfoliative glaucoma, in which polymorphisms of the LOXL1 gene are strongly associated with this
condition in multiple populations (see Chapter 15).
In addition, molecular genetics is helping to associate seemingly disparate diseases. For example, Rieger
syndrome and iris hypoplasia can arise from mutations in the same gene on 4q25 (PITX2) (7). Similarly,
juvenile open-angle glaucoma and iridogoniodysgenesis can be caused by mutations in the FKHL7 gene
on 6p25 (8, 9). Improved understanding of the molecular etiology of various glaucomas will permit
detailed reclassification of these disorders.
CLASSIFICATION BASED ON MECHANISM
An understanding of the initial events in each form of glaucoma will eventually allow for an improved
classification system and a rationale for early glaucoma intervention. Until that information becomes
available, however, most treatment strategies will continue to focus on IOP and depend on an
understanding of the mechanisms of aqueous outflow obstruction.
As noted previously, one disadvantage of a classification based on the mechanism of aqueous outflow
obstruction is that it ignores the causes unrelated to pressure. In addition, many of the glaucomas have
more than one mechanism of outflow obstruction at different times in the course of the disease. As a
result, some glaucomas must be classified under more than one mechanistic heading. It is for this reason
that a classification based on initial events, rather than mechanisms of outflow obstruction, is used for
organizing the chapters on clinical forms of glaucoma in this text.
On the other hand, the mechanistic classification has distinct advantages. First, our understanding of the
mechanisms of aqueous outflow obstruction is in many cases more complete than our knowledge of the
initial events. Second, because most current treatment strategies are directed at reducing IOP, an
understanding of the mechanism that leads to aqueous outflow obstruction is important in developing a
rationale for controlling the pressure in each form of glaucoma.
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Barkan (10) first recognized the distinction between open-angle and closed-angle forms of glaucoma,
which led to the basis for the mechanistic classification of the glaucomas (Fig. 7.1). A third group of
glaucomas that does not fit well into either the open- or closed-angle mechanisms is the developmental
glaucomas. The mechanistic classification, therefore, can be divided into three categories: (a) openangle
glaucoma mechanisms, (b) angle-closure glaucoma
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mechanisms, and (c) developmental anomalies of the anterior chamber angle (Table 7.3 and Fig. 7.2).
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Figure 7.1 The angle of the anterior chamber is formed by the cornea and iris. A: The typical
configuration in open-angle forms of glaucoma. B: The narrow angle that typically precedes most forms
of angle-closure glaucoma.
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Open-Angle Glaucoma Mechanisms
The open-angle mechanisms are those in which the anterior chamber angle structures (i.e., trabecular
meshwork, scleral spur, and ciliary body band) are visible by gonioscopy. The elements obstructing
aqueous outflow may be located on the anterior chamber side of the trabecular meshwork (pretrabecular
mechanisms); in the trabeculum (trabecular mechanisms); or distal to the meshwork, in the Schlemm
canal, or further along the aqueous drainage system (posttrabecular mechanisms).
In the pretrabecular mechanisms, a translucent membrane extends across the open iridocorneal angle,
leading to the obstruction of aqueous outflow. This obstructive element may be a fibrovascular
membrane, an endothelial layer with a Descemet-like membrane, an epithelial membrane, a connective
tissue membrane, or an inflammatory-related membrane.
With the trabecular mechanisms, the obstruction to aqueous outflow is located in the trabecular
meshwork. The chronic openangle glaucomas are included in this category, although the precise
mechanisms of the obstruction are unknown. As previously noted, this category of the glaucomas likely
represents distinct entities with differing mechanisms of outflow obstruction. In other glaucomas with a
trabecular mechanism, there may be a “clogging” of the meshwork with red blood cells, macrophages,
neoplastic cells, pigment particles, protein, lens zonules, viscoelastic agents, or vitreous. In still other
cases, obstruction to outflow may result from acquired alterations of the trabecular meshwork tissue
such as obstruction associated with inflammatory conditions, trauma with subsequent scarring, and toxic
reactions associated with intraocular foreign bodies. Steroid-induced glaucoma and certain glaucomas
associated with systemic diseases can lead to obstruction of aqueous outflow in the trabecular
meshwork.
With the posttrabecular mechanisms, obstruction to aqueous outflow may result from increased
resistance in the Schlemm canal due to collapse or absence of the canal, or, in patients with sickle cell
anemia, from obstruction of the canal itself with sickled red blood cells. The role of collector channel
obstruction remains a largely unexplored possibility. Perhaps the most common cause of the
posttrabecular cases is elevated episcleral venous pressure.
Angle-Closure Glaucoma Mechanisms
The angle-closure mechanisms include situations in which the peripheral iris is in apposition to the
trabecular meshwork or peripheral cornea. The peripheral iris may either be “pulled7rdquo; (anterior
mechanisms) or “pushed” (posterior mechanisms) into this position.
In the anterior mechanisms of angle-closure glaucoma, an abnormal tissue bridges the anterior chamber
angle and subsequently undergoes contraction, pulling the peripheral iris into the iridocorneal angle.
Examples of the contracting tissue include a fibrovascular membrane, an endothelial layer with a
Descemet-like membrane, and inflammatory precipitates.
With the posterior mechanisms, pressure behind the iris, lens, or vitreous causes the peripheral iris to be
pushed into the anterior chamber angle. This may occur with or without pupillary block.
Posterior mechanisms with pupillary block include pupillary block glaucoma (as previously described).
Functional apposition between the peripupillary iris and lens in this condition increases resistance of
aqueous humor flow into the anterior chamber, resulting in a relative increase in posterior chamber
pressure and forward bowing of the peripheral iris. The functional apposition in these patients is due to a
genetically influenced configuration of the anterior ocular segment. In other conditions, the same
functional apposition may result from an acquired forward shift of the lens (e.g., intumescent cataract or
subluxed lens). In still other cases, a pupillary block
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may be due to posterior synechia associated with inflammation of the anterior ocular segment. In each of
these conditions, apposition between the iris and the lens, intraocular lens, or vitreous obstructs the flow
of aqueous humor into the anterior chamber, resulting in increased pressure in the posterior chamber and
forward bowing of the peripheral iris into the anterior chamber angle.
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Table 7.3 Classification of the Glaucomas Based on Mechanisms of Outflow Obstructiona
OPEN-ANGLE GLAUCOMA MECHANISMS
A. Pretrabecular (membrane overgrowth)
1. Fibrovascular membrane (neovascular glaucoma)
2. Endothelial layer, often with Descemet-like membrane
a. Iridocorneal endothelial syndrome
b. Posterior polymorphous dystrophy
c. Penetrating and nonpenetrating trauma
3. Epithelial downgrowth
4. Fibrous ingrowth
5. Inflammatory membrane
a. Fuchs heterochromic iridocyclitis
b. Luetic interstitial keratitis
B. Trabecular (occlusion of intertrabecular spaces)
1. Idiopathic
a. Chronic open-angle glaucoma
b. Steroid-induced glaucoma
2. Obstruction of trabecular meshwork
a. Red blood cells
(1) Hemorrhagic glaucoma
(2) Ghost cell glaucoma
b. Macrophages
(1) Hemolytic glaucoma
(2) Phacolytic glaucoma
(3) Melanomalytic glaucoma
c. Neoplastic cells
(1) Malignant tumors
(2) Neurofibromatosis
(3) Nevus of Ota
(4) Juvenile xanthogranuloma
d. Pigment particles
(1) Pigmentary glaucoma
(2) Exfoliation syndrome
(3) Uveitis
(4) Malignant melanoma
e. Protein
(1) Uveitis
(2) Lens-induced glaucoma
f. Viscoelastic agents
g. a-Chymotrypsin-induced glaucoma
h. Vitreous
3. Alterations of the trabecular meshwork
a. Edema
(1) Uveitis (trabeculitis)
(2) Scleritis and episcleritis
(3) Alkali burns
b. Trauma (angle recession)
c. Intraocular foreign bodies (hemosiderosis, chalcosis)
C. Posttrabecular
1. Obstruction of Schlemm canal
a. Collapse of canal
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b. Obstruction of Schlemm canal (e.g., sickled red blood cells)
2. Elevated episcleral venous pressure
a. Carotid-cavernous fistula
b. Cavernous sinus thrombosis
c. Retrobulbar tumors
d. Thyrotropic exophthalmos
e. Superior vena cava obstruction
f. Mediastinal tumors
g. Sturge-Weber syndrome
h. Elevated episcleral venous pressure
ANGLE-CLOSURE GLAUCOMA MECHANISMS
A. Anterior (“pulling” mechanism)
1. Contracture of membranes
a. Neovascular glaucoma
b. Iridocorneal endothelial syndrome
c. Posterior polymorphous dystrophy
d. Penetrating and nonpenetrating trauma
2. Contracture of inflammatory precipitates
B. Posterior (“pushing” mechanism)
1. With pupillary block
a. Pupillary block glaucoma
b. Lens-induced mechanisms
(1) Intumescent lens
(2) Subluxation of lens
(3) Mobile lens syndrome
c. Posterior synechiae
(1) Iris-intraocular lens block in pseudophakia
(2) Uveitis with posterior synechiae
(3) Iris-vitreous block in aphakia
2. Without pupillary block
a. Plateau iris syndrome
b. Ciliary block (malignant) glaucoma
c. Lens-induced mechanisms
(1) Intumescent lens
(2) Subluxation of lens
(3) Mobile lens syndrome
d. After lens extraction (forward vitreous shift)
e. Secondary to scleral buckling surgery
f. Secondary to panretinal photocoagulation
g. Central retinal vein occlusion
h. Intraocular tumors
(1) Malignant melanoma
(2) Retinoblastoma
i. Cysts of the iris and ciliary body
j. Retrolenticular tissue contracture
(1) Retinopathy of prematurity (retrolental fibroplasia)
(2) Persistent hyperplastic primary vitreous
DEVELOPMENTAL ANOMALIES OF THE ANTERIOR CHAMBER ANGLE
A. High insertion of anterior uvea
1. Congenital (infantile) glaucoma
2. Juvenile glaucoma
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3. Glaucomas associated with other developmental anomalies
B. Incomplete development of trabecular meshwork/Schlemm canal
1. Axenfeld-Rieger syndrome
2. Peters anomaly
3. Glaucomas associated with other developmental anomalies
C. Iridocorneal adhesions
1. Broad strands (Axenfeld-Rieger syndrome)
2. Fine strands that contract to close angle (aniridia)
aClinical examples cited in this table do not represent an all-inclusive list of the glaucomas.
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Figure 7.2 Open-angle forms of glaucoma may be of the pretrabecular (A), trabecular (B), or
posttrabecular (C) type. Angle-closure forms of glaucoma may be of the anterior “pulling” type (D) or
the posterior “pushing” type. The latter may occur with (E) or without (F) pupillary block. Arrows
indicate location of force pushing the iris or lens-iris diaphragm forward. A third basic mechanism is
developmental abnormalities of the anterior chamber angle.
In the posterior mechanisms of angle-closure glaucoma without pupillary block, increased pressure in
the posterior portion of the eye pushes the lens-iris or vitreous-iris diaphragm forward. Examples
include malignant (ciliary block) glaucoma, plateau iris syndrome, intraocular tumors, cysts of the iris
and ciliary body, and contracture of retrolenticular tissue.
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Developmental Anomalies of the Anterior Chamber Angle
These glaucomas are not readily separated into open-angle and angle-closure mechanisms, but typically
represent incomplete development of structures in the conventional aqueous outflow pathway. Clinically
recognized developmental defects include a high insertion of the anterior uvea, as in congenital
(infantile) glaucoma, and many of the glaucomas associated with other developmental abnormalities. In
other cases, the defect may manifest as an incompletely developed trabecular meshwork or Schlemm
canal (e.g., Peters anomaly) or as iridocorneal adhesions (e.g., Axenfeld-Rieger syndrome).
KEY POINTS
The many clinical forms of glaucoma are commonly classified by (a) cause or (b) mechanism. The
former is based on the underlying disorder that leads through a multistage pathway to alterations
in aqueous humor dynamics or optic neuropathy with subsequent visual field loss.
The mechanistic classification is based on alterations in the anterior chamber angle, which may
result from the underlying initiating abnormality and lead to the elevated IOP. The mechanistic
classification is divided into open-angle and angle- closure mechanisms and developmental
anomalies of the anterior chamber angle. These groups are then subdivided according to the
underlying cause and specific structural alterations.
The ongoing revolution in molecular genetics will likely change our current understanding of
disease. This new knowledge will increasingly guide the classification of many types of glaucoma
(as discussed in Chapter 8).
REFERENCES
1. Pavlin CJ, Ritch R, Foster FS. Ultrasound biomicroscopy in plateau iris syndrome. Am J Ophthalmol.
1992;113:390-395.
2. Alward WLM. Molecular genetics of glaucoma: effects on the future of disease classification. In: Van
Buskirk EM, Shields MB, eds. 100 Years of Progress in Glaucoma. Philadelphia, PA: Lippincott-Raven;
1997:143.
3. Semina EV, Reiter R, Leysens NJ, et al. Cloning and characterization of a novel bicoid-related
homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet. 1996;14:392-399.
4. Mirzayans F, Gould DB, Heon E, et al. Axenfeld-Rieger syndrome resulting from mutation of the
FKHL7 gene on chromosome 6p25. Eur J Hum Genet. 2000;8(1):71-74.
5. Phillips JC, del Bono EA, Haines JL, et al. A second locus for Rieger syndrome maps to chromosome
13q14. Am J Hum Genet. 1996;59(3): 613-619.
6. Allingham RR, Liu Y, Rhee DJ. The genetics of primary open-angle glaucoma: a review. Exp Eye
Res. 2009;88:837-844.
7. Héon E, Sheth BP, Kalenak JW, et al. Linkage of autosomal dominant iris hypoplasia to the region of
the Rieger syndrome locus. Hum Mol Genet. 1995;4:1435-1439.
8. Nishimura D, Swiderski R, Alward W, et al. The forkhead transcription factor gene FKHL7 is
responsible for glaucoma phenotypes which map to 6p25. Nat Genet. 1998;19:140-147.
9. Mears AJ, Jordan T, Mirzayans F, et al. Mutations of the forkhead/winged-helix gene, FKHL7, in
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patients with Axenfeld-Rieger anomaly. Am J Hum Genet. 1998;63:1316-1328.
10. Barkan O. Glaucoma: classification, causes, and surgical control—results of microgonioscopic
research. Am J Ophthalmol. 1938;21:1099-1117.
Say thanks please
8 - Molecular Genetics and Pharmacogenomics of the Glaucomas
> Table of Contents > SECTION II - The Clinical Forms of Glaucoma > 8 - Molecular Genetics and
Pharmacogenomics of the Glaucomas
8
Molecular Genetics and Pharmacogenomics of the Glaucomas
This chapter introduces the reader to the shift from a “single gene, rare disease” concept to a “complex
and multiple gene disease” model. By reading this chapter, you will learn about the expectations of how
genomic testing will pave the way to individualized treatment for patients with various forms of
glaucoma. It begins with highlighting the difference between single genes, which when mutated may
result in striking clinical phenotypes (e.g., Axenfeld-Rieger syndrome), versus genes that may have
DNA sequence variants (known as polymorphisms) that, with or without environmental contributions,
can be associated with more common forms of glaucoma (e.g., exfoliation syndrome). Insights into the
etiology and pathogenesis of various forms of glaucoma gleaned from analysis of DNA, RNA, or
protein are then described. These insights will likely lead to new targets for glaucoma therapy that are
beyond simply lowering intraocular pressure (IOP). The chapter ends with a discussion of
pharmacogenomics and how genomic testing may help clinicians develop more rational, personalized
treatment for their patients.
This chapter begins with three cases to illustrate the promising application of molecular medicine in the
clinical context.
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Figure 8.1 Optic disc photos (A) showing very thin neuroretinal rim in each eye. Visual fields (B)
showing advanced nerve fiber bundle defects encroaching on fixation in the left visual field and within
10 degrees in the right visual field.
CASES
Please review each of these clinical scenarios and keep them in mind as you go through this chapter.
Comments will be made on each of these cases later in the chapter.
Case 1
A 17-year-old female patient presents to your office reporting blurred and gradually decreasing vision.
On examination, her visual acuity is 20/20 OU and the IOP is 30 mm Hg OU. Her angles are open and
normal by gonioscopy Central corneal thicknesses measure 503 µm OD and 498 µm OS. She has neartotal cupping of both optic nerves (Fig. 8.1A). Visual field testing demonstrates defects within 10
degrees of fixation OU (Fig. 8.1B).
On inquiring further, you learn that her mother and sister also have glaucoma that developed relatively
early in life. The mother is blind in one eye, and the sister's eyes are stable after having glaucoma
surgery in both eyes.
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Figure 8.2 Appearance of the anterior and posterior segments of the mother's right eye.
The patient asks several insightful questions:
What do I have?
Will I go blind if I don't receive treatment, and what is my best treatment option?
What are the chances that any future biological children of mine would also get this disease?
Can anything be done other than medications and surgery to treat my condition?
Case 2
A 40-year-old Scandinavian man has a mother with advanced exfoliative glaucoma (Fig. 8.2). He wants
to know his chances of developing the same condition.
Case 3
A 68-year-old woman presents for advice about her glaucoma diagnosis and its impact on her children.
She brings along her personal “smart card” that contains her medical history, past visual fields, optic
disc imaging, and genomic sequence.
At diagnosis, her IOPs measured 33 mm Hg in both eyes, and her central corneal thickness
measurements were 584 µm OD and 566 µm OS. She was otherwise asymptomatic, and she was treated
for glaucoma on the basis of the appearance of the neuroretinal rim of her optic disc (Fig. 8.3).
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Figure 8.3 Case demonstrating progression of glaucoma based on right optic disc photos (A) and right
visual fields (B) over 18 years despite medical and surgical treatments with IOP reduction and
fluctuation between 7 and 13 mm Hg. (Modified from Moroi SE, Richards JE. Glaucoma and genomic
medicine. Glaucoma Today. 2008;1:16-24, with permission.)
Over the following 18 years, her IOPs fluctuated between 7 mm Hg and 13 mm Hg with medical and
surgical treatments. Despite this management, she developed progressive cupping of the optic disc and
visual field loss (Fig. 8.3, center and right) over time. She asks: “Will the same thing happen to my
children?”
THE HUMAN GENOME
Genes for glaucoma are found throughout the human genome (Fig. 8.4). There are approximately 20,500
genes encoded in the 6 billion base pairs that make up human DNA distributed on 46 chromosomes (1).
In addition, 37 “mitochondrial” genes are encoded in the circular mitochondrial DNA that is inherited
through the mother. An offshoot of the Human Genome Project (http://www.genome.gov/10001772)
was the International HapMap project (http://www.hapmap.org/), which permitted the identification and
cataloguing of genetic sequence variants among individuals across diverse populations. These variants
are known as single-nucleotide polymorphisms, or SNPs (pronounced “snips”). These SNPs are
recognized as markers for
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chromosomal regions where genetic variants are shared among individuals of a given ethnic group. By
taking advantage of these conserved DNA blocks marked by these SNPs, early successes have shown
promise to identify certain SNPs as potential markers for disease. Future research may shed further
insight on disease onset, disease severity, and treatment response, thus paving the way toward the advent
of “personalized medicine.”
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Figure 8.4 Chromosomal location of genes and loci for various forms of open- or closed-angle glaucoma
are found throughout the human genome. Only the Y chromosome is believed not to harbor a gene or
locus for glaucoma.
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Figure 8.5 Overview of application of linkage and association approaches to identify genes as markers
for complex diseases and quantitative traits. The appropriate approach selected for a study depends on
the frequency of the genetic variant and the penetrance of the disease mutation. (Modified from Moroi
SM, Raoof DA, Reed DM, et al. Progress toward personalized medicine for glaucoma. Expert Rev
Ophthalmol. 2009;4(2):145-161.)
Mendelian (“Single Gene”) versus Non-Mendelian (Complex) Diseases
Mendelian disorders are typically rare diseases that follow Mendelian patterns of inheritance—the laws
of segregation of alleles and the law of independent assortment. Common examples of Mendelian
patterns of inheritance include autosomal-dominant, autosomal-recessive, and X-linked inheritance.
Clinicians are familiar with these rare or uncommon clinical disorders because of the striking clinical
phenotypes, such as juvenile open-angle glaucoma (JOAG), illustrated in Case 1, and others involving
anterior segment dysgenesis, such as Axenfeld-Rieger syndrome. The genetics of such cases represent
the “single gene—single disease” model.
In contrast, non-Mendelian, or complex, disorders do not follow the classical rules of Mendelian
inheritance. Examples include quantitative traits that result from the additive effects of many genetic or
environmental effects, polygenic traits that happen only if defects are present in more than one gene,
traits displaying incomplete penetrance, codominant inheritance in which each of the three genotypic
combinations for an allele have a different phenotype, imprinting effects caused by chemical
modifications to the DNA, or mitochondrial inheritance. Representative conditions and diseases include
exfoliation, normal-tension glaucoma, and chronic open-angle glaucoma (COAG).
There are various approaches used to identify a single gene or multiple genes that are involved in
inherited disorders. These approaches can also be applied to the discovery of genes underlying treatment
outcomes in the field of pharmacogenetics (how an individual's genes affect the way the individual's
body responds to a medication or treatment) and pharmacogenomics (the study of drug responses in the
context of the entire genome). (The topic of pharmacogenetics and pharmacogenomics is addressed later
in this chapter.) The selection of a particular approach or method depends on the frequency of the
disease mutation and the penetrance of the mutation (the frequency with which the presence of a
particular genotype in an organism results in the corresponding phenotype) (Fig. 8.5).
Two common approaches used to identify genetic variants that contribute to inherited diseases are
termed linkage analysis and association analysis. Linkage studies involve genetic mapping based on the
cotransmission of genetic markers and phenotypes from one generation to the next in one or more
families. Association studies involve comparison of cases to controls to assess the relative contribution
of genetic variants or environmental effects to the trait being studied. In addition, association studies
may also be designed to study a quantitative trait, such as IOP, in a single large cohort.
Primary Glaucomas
Primary Congenital Glaucoma
Primary congenital glaucoma (PCG) is an uncommon disease with a frequency ranging from 1 in 1250
(among the Roma population of Slovakia) to 1 in 10,000 (2). The anterior segment often reveals an
anteriorly inserted iris, with a maldeveloped angle and trabecular meshwork. Most cases of PCG are
sporadic; in familial cases, autosomal-recessive inheritance is most common. Most of these patients
require surgical management because current glaucoma medications and lasers are generally ineffective
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for this form of glaucoma. Two loci have been identified for the infantile form of congenital glaucoma:
2p211 and 1p36. The gene within the 2p21 locus, which accounts for the majority of familial cases, was
identified in 1997 and encodes the protein cytochrome P4501B1 (CYP4501B1).
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Although the ocular substrate for cytochrome P450B1 remains unknown, this enzyme is likely to play an
important role in ocular development (3). Libby and colleagues have shown that mutant Cyp1b1-/- mice
deficient in cytochrome P450B1, where both copies of the Cyp1b1 gene are nonfunctional, develop
focal defects in the anterior chamber angle, including an increase in basal lamina of the trabecular
meshwork and a small or absent Schlemm canal. Other experiments testing for genes that enhance or
suppress angle abnormalities in Cyp1b1 identified the tyrosinase gene (Tyr) as a modifier whose
deficiency exacerbates defects in Cyp1b1 mutant mice (3). Eyes lacking cytochrome P450B1 and
tyrosinase demonstrated severe dysgenesis that was alleviated by the administration of L-DOPA, a
normal product of tyrosinase. Thus, a pathway involving tyrosinase appears to be important in anterior
chamber angle development.
Juvenile-Onset Open-Angle Glaucoma
JOAG is an autosomal-dominant form of COAG with an early age of onset. It is characterized by
extremely high IOP with subsequent damage to the optic nerve and visual field. Affected eyes are often
myopic. This disease usually begins between the ages of 4 and 35 years, often in individuals with a
strong family history. In patients with JOAG, response to drug or laser treatment is generally poor and
surgical intervention is often required.
JOAG was first linked to chromosome 1q21-31 by Sheffield and colleagues in 1993. Four years later,
mutations were found in the responsible gene, the trabecular meshwork glucocorticoid response gene
(TIGR, later renamed myocilin (4)). At least five loci are now mapped for JOAG. Of all cases of JOAG,
approximately 10% to 20% are caused by mutations in the myocilin gene (5).
Revisiting Case 1
The phenotype is classic for JOAG. A mutation in the myocilin gene was suspected, and hence the gene
was sequenced. A single base change, C?T (Pro370Leu) in exon 3, was found (6). This missense
mutation was found in the mother and the two affected daughters, but not in the father. Armed with this
information, one can now respond to the patient's queries:
What do I have?
JOAG
Will I go blind if I don't receive treatment, and what is my best treatment option?
The Pro370Leu mutation is aggressive and leads to blindness if the pressure elevation is not
treated. The best treatment option at present is aggressive IOP lowering with medication initially,
and then surgery (e.g., trabeculectomy with an antimetabolite) if medical treatment does not lower
the IOP to an appropriate target range.
What are the chances that any future biologic children of mine would also get this disease?
JOAG is autosomal dominant with high penetrance, so the risk is approximately 50%.
Can anything be done other than medications and surgery to treat my condition?
Not at present, but additional strategies may become possible in the future, including gene
replacement and alteration of the trabecular meshwork cellular and extracellular milieu to enhance
outflow facility.
Adult-Onset Chronic Open-Angle Glaucoma
The high prevalence of COAG, variability in age of onset, and nonpenetrance (lack of phenotypic
expression of a disease despite carrying the genetic mutation) in some pedigrees indicate that most cases
of COAG are not inherited as a single-gene defect but as a “complex” trait that does not demonstrate
simple Mendelian inheritance. Interplay among various environmental and genetic factors, or among
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multiple genes, results in a high degree of variability in phenotypic expression and disease severity that
makes linkage analysis extremely challenging. To date, linkage studies on families with COAG provide
strong evidence for genetic heterogeneity. At least 11 loci have been identified, along with three genes
(myocilin, optineurin, and WDR36) (Table 8.1).
Additional evidence for genetic susceptibility comes from polymorphisms of genes suspected of playing
a role in glaucoma. Polymorphisms in the genes coding for the ß-adrenergic receptors ADRB1 and
ADRB2 expressed in the trabecular meshwork and ciliary body have been examined and may influence
the pathophysiology of COAG in both COAG and normal-tension glaucoma in Japanese patients (7).
However, the ADRB2 gene does not appear to be a “causative” COAG genetic risk, as shown in an
appropriately powered study comparing controls and COAG cases among white individuals and persons
of African ancestry (8). There may also be susceptibility genes that are essential to permit other genes or
environmental factors to lead to glaucoma. For example, the OPA1 gene and apolipoprotein E gene have
been associated with normal-tension glaucoma and COAG, respectively (9, 10). It remains to be seen
what role these diseaseassociated polymorphisms will play in patients with glaucoma.
Angle-Closure Glaucoma
There have been a growing number of investigators who have explored the familial basis of angleclosure glaucoma using both traditional Mendelian study design approaches and application of ocular
biometry for quantitative trait design approach. In certain regions of the world, angle-closure glaucoma
is the most common form of glaucoma, so it is important to understand the genetic mechanisms involved
in this condition, which can be amenable to treatment with laser approaches.
Using a combination of a genetic approach applied to an epidemiology study, Hu found a sixfoldincreased risk for angle-closure glaucoma among persons with any family history of angle-closure
glaucoma in his population-based survey in Shunyi County, Beijing, which supports a genetic factor
(11). Using a quantitative trait approach, a study of axial anterior chamber depth in twins (without angleclosure glaucoma) indicated that about 70% of the variance in dizygotic twins could be attributable to a
genetic component (12). A biometric study showed a relatively shallow anterior chamber depth in
siblings, children, nephews, nieces, and grandchildren of angle-closure
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glaucoma probands (13). A heritability of 70% was found in this study, indicating that about two thirds
of the age- and sexindependent variation of anterior chamber depth is inherited. Furthermore, Lowe has
suggested that inheritance of a shallow anterior chamber is polygenic with a threshold effect so that the
action of a large number of grouped or independently inherited genes results in varying degrees of
anterior chamber shallowing (14). A Chinese study of families with angle-closure glaucoma and shallow
anterior chambers concluded that the inheritance of a shallow anterior chamber may be a genetically
heterogeneous trait and influenced by sex with autosomaldominant inheritance in subgroups (15).
Table 8.1 Summary of Genes and Loci Associated with Glaucomaa
Chromosome Symbolb
Phenotype
1
PLOD1
Ehlers-Danlos syndrome, type VI
1
(GLC3B)
PCG, type B
Posterior polymorphous corneal dystrophy 2, Fuchs endothelial corneal
1
COL8A2
dystrophy
1
POMGNT1 Muscle-eye-brain disease
1
COL11A1
Marshall syndrome, Stickler syndrome II
1
MYOC
JOAG
2
CYP1B1
PCG, Peters anomaly, COAG, JOAG
2
(GLC1H)
High-tension open-angle glaucoma
2
(GLC1B)
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3
3
3
4
4
(GLC1L)
(GLC1C)
OPA1
IDUA
SLC4A4
4
5
5
5
5
6
6
PITX2
ARSB
VCAN
(GLC1M)
WDR36
COL11A2
FOXC1
6
7
7
8
8
8
9
9
9
9
9
9
10
10
10
10
11
11
11
11
11
11
12
13
13
14
14
14
14
14
14
15
15
15
15
16
GJA1
(GLC1F)
(GPDS1)
KTWS
(GLC1D)
GDF6
GLIS3
(GLC1J)
PTCH1
FKTN
LMX1B
POMT1
OPTN
ZEB1
PAX2
PITX3
PAX6
SBF2
(NNO1)
MFRP
C1QTNF5
LRP5
COL2A1
RIEG2
MCORc
SIX6
POMT2
LTBP2
VSX2
MCOPc
(GLC3D)
(GLC1I)
FBN1
LOXL1
(GLC1N)
CREBBP
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Open-angle glaucoma
Optic nerve atrophy, normal-tension open-angle glaucoma
Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome
Renal tubular acidosis, mental retardation, glaucoma
Iridogoniodysgenesis, type 2; Rieger type 1; Peters anomaly; ring
dermoid of cornea
Mucopolysaccharidosis VI, Maroteaux-Lamy syndrome
Wagner syndrome 1
Open-angle glaucoma
Open-angle glaucoma
Stickler syndrome III, Weissenbacher-Zweymuller syndrome
Iridogoniodysgenesis 1, anterior segment mesenchymal dysgenesis,
Rieger anomaly, Axenfeld anomaly, iris hypoplasia, juvenile glaucoma
Oculodentodigital dysplasia, microphthalmia
Pigment dispersion 1
Klippel-Trenaunay-Weber syndrome
Microphthalmia, isolated 4
Neonatal diabetes mellitus and hypothyroidism, PCG
JOAG
Basal cell nevus syndrome
Walker-Warburg syndrome
Nail-Patella syndrome
Normal-tension and high-tension open-angle glaucoma
Posterior polymorphous corneal dystrophy 3
Renal-coloboma or papillorenal syndrome, “morning glory” optic nerve
Anterior segment dysgenesis
Aniridia II, Peters anomaly, “morning glory” optic nerve, coloboma
Charcot-Marie-Tooth disease type 4B2
Nanophthalmos 1
Nanophthalmos 2
Late-onset retinal degeneration and long anterior zonules
Osteogenesis imperfecta, ocular form
Stickler syndrome I
Rieger syndrome 2
Congenital microcoria
Microphthalmia with cataract 2
PCG
Microphthalmos
Microphthalmos
PCG
Weill-Marchesani syndrome, ectopia lentis, Marfan syndrome
Risk allele for exfoliation glaucoma
JOAG
Rubinstein-Taybi syndrome
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17
NF1
Neurofibromatosis 1
18
RAX
Microphthalmos
19
ADAMTS10 Weill-Marchesani syndrome
19
FKRP
19
(GLC1O)
COAG
20
(GLC1K)
JOAG, 3
20
VSX1
Posterior polymorphous corneal dystrophy 1
21
CBS
Homocystinuria, ectopia lentis
22
NF2
Neurofibromatosis 2
22
LARGE
X
NDP
Coats disease, uveitis, secondary glaucoma, Norrie disease
X
BCOR
Microphthalmia, syndromic 2
X
HCCS
Microphthalmia, syndromic 7
X
OCRL
Lowe oculocerebrorenal syndrome
c
X
MRXSA
Armfield X-linked mental retardation syndrome
aHUGO symbols are used (www.hugo-international.org); information cross-checked with GeneCards,
version 2.39 (www.genecards.org, cross-referenced to HUGO, Entrez Gene, UniProt/Swiss-Prot,
UniProt/TrEMBL, OMIM, GeneLoc, Ensembl).
b Symbols in
parentheses are locus symbols. Unless otherwise noted, all other symbols are HUGOapproved gene symbols.
c The symbol
is based on Entrez Gene because there is no approved symbol in HUGO. COAG, chronic
open-angle glaucoma; JOAG, juvenile open-angle glaucoma; PCG, primary congenital glaucoma.
In a rare phenotype on the spectrum of angle-closure glaucoma is nanophthalmos, which represents an
ocular phenotype characterized by a biometrically small eye with relatively normal lens volume. Such
individuals are at increased risk for angle- closure glaucoma due to a crowded anterior segment, uveal
effusions due to thickened sclera, and aqueous misdirection (see Chapter 26). In a large family with 22
affected family members with highly penetrant nanophthalmos (16), a locus called NNO1 was mapped
to chromosome 11. The gene has not yet been identified.
Using a molecular approach, a study quantifying SPARC protein (secreted protein, acidic, and rich in
cysteine) in iridectomy specimens of eyes with chronic angle closure found that these irides had a
significantly higher SPARC and collagen 1 protein content compared with nonglaucomatous eyes and
eyes with COAG (17). The data suggest that SPARC could play a role in the development of angleclosure glaucoma by influencing the biomechanical properties of the iris through a change in
extracellular matrix organization.
It has also been suggested that environmental triggers may alter anterior chamber depth or degree of
pupillary block. These are associated with angle-closure glaucoma, including neural or humoral
response to fatigue, mental stress, infection, and trauma (18).
Secondary Glaucomas
Developmental Glaucomas
Developmental glaucomas are secondary to morphologic malformations of the anterior segment and are
relatively rare. Importantly, however, developmental abnormalities of the ocular drainage structures are
not always clinically detectable, and abnormal development may affect the metabolism and function of
the drainage structures without disturbing morphology. Glaucomas and known genes associated with
developmental disorders are listed as part of Table 8.1. It is important to note that clinical findings
overlap considerably, even within families, and mutations in the same gene can
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cause a range of phenotypes. The primary causative genes that have been identified are transcription
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factor-related genes: PITX2, PITX3, and FOXC1.
Pigmentary Glaucoma
Several investigators have demonstrated autosomal-dominant inheritance for the pigment dispersion
syndrome (PDS) (19, 20 and 21). In 1997, Andersen and colleagues described four autosomaldominant
PDS families and reported localization of a gene to chromosome 7q35-36 (22). The disorder is
genetically heterogeneous, and further studies are under way to determine whether additional loci exist
and to find the gene (or genes) involved. DBA/2J mice appear to develop a form of pigmentary
glaucoma caused by mutations in the glycoprotein (transmembrane) nmb gene, Gpnmb, and the
tyrosinase-related protein 1 gene, Tyrp1. As both genes encode melanosomal proteins, it has been
hypothesized that these mutations permit toxic intermediates of pigment production to leak from
melanosomes (23). A study examining glaucoma patients with PDS for DNA sequence variants in
TYRP1 did not find an association (24).
Exfoliation Syndrome
Evidence supports the concept that exfoliation is an inherited microfibrillopathy involving transforming
growth factor-1, oxidative stress, and impaired cellular protection mechanisms as key factors (Fig.
15.12). In a study in the Icelandic and Swedish populations, a common genetic variant was identified as
a major risk factor for exfoliation syndrome and glaucoma (25). Polymorphisms in the coding region of
the gene lysyl oxidase-like 1 (LOXL1), located on chromosome 15q24, are associated with exfoliation
and exfoliative glaucoma in these and other populations. The disease-associated polymorphisms are
found in virtually all individuals with exfoliation within populations studied to date.
LOXL1 is one of many enzymes essential for the formation of elastin fibers: It plays a role in modifying
tropoelastin, the basic building block of elastin, and catalyzes the process for monomers to cross-link
and form elastin. Although LOXL1 is a major risk factor for exfoliation syndrome and exfoliative
glaucoma, evidence suggests that additional genetic or environmental factors will be identified that
influence disease expression and severity. One example is a study of white persons in Australia with a
ninefold-lower lifetime incidence of exfoliative glaucoma compared with Scandinavian populations that
demonstrated a similar allelic architecture at the LOXL1 locus (26). This suggests that unidentified
genetic or environmental factors independent of LOXL1 strongly influence the phenotypic expression of
the syndrome.
The disease-associated LOXL1 variant is extremely common and is found in up to 90% of affected and
unaffected individuals worldwide. For this reason, genetic testing is of limited clinical value at this time
(27).
Revisiting Case 2
The discovery of the variants in the LOXL1 gene has the potential to lead to more exact diagnosis, better
monitoring of glaucoma suspects, improved knowledge of pathogenesis, and eventually more effective
treatment. Despite the importance of the identification of LOXL1 as a major contributor to exfoliation
syndrome and exfoliative glaucoma, given the high frequency of disease-associated polymorphisms in
the population, DNA testing is not clinically useful at this time.
Systemic Diseases Associated with Glaucoma
A number of ocular disorders that have been linked are associated with open-angle forms of glaucoma as
part of their phenotype. These are listed in Table 8.1. In addition, a number of systemic disorders are
associated with open-angle forms of glaucoma (e.g., nail-patella syndrome and Marfan syndrome), and
those for which the gene has been localized or identified are listed in Table 8.1.
GENETICS AND INSIGHTS INTO DISEASE MECHANISMS
After identifying genes that are causative for glaucoma and genes that contribute to risk factors for
glaucoma, we will elucidate disease mechanisms for glaucoma. This will also involve well-established
mouse-model systems for glaucoma that will allow studies on specific biochemical pathways that
ultimately cause glaucoma (28). To reach an in-depth understanding of role of these genes among these
pathways, however, it will be essential to combine the tools of genomics, molecular biology,
developmental biology, bioinformatics, and computational biology. This should ultimately lead to a
better understanding of the normal physiology of the trabecular meshwork, optic nerve, ganglion cells,
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and other glaucoma-relevant tissues. Improved understanding of the state of the eye in disease and
health will facilitate the rational development of drugs tailored to specific subtypes of glaucoma.
PHARMACOGENETICS, PHARMACOGENOMICS, AND THE PROMISE OF “PERSONALIZED
MEDICINE”
Although all this information on genetics may appear daunting to the clinician, it is important to put this
genomic technology in perspective. All of this genomic information, and the anticipated proteomic and
metabolomic information, will not substitute for solid clinical history-taking skills, observation,
assessment, and development of a treatment plan for the individual patient. However, at present, using
our clinical acumen, our treatment approach is a trial-and-error approach by recommending a
medication, laser, or surgery with an expected optimal treatment outcome. There is great optimism that
genetic profiling will help target patients with glaucoma to individualized treatments on the basis of
validated disease-risk alleles, validated pharmacogenetic markers, and specific behavioral modification.
Thus, one may view these newer technology advances to take the guesswork out of the treatment plan,
with
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the expectation of improved efficacy because the optimal treatment is specified for certain individual
profiles and for decreased adverse events to treatment because it will not be recommended in a
susceptible individual.
It is important to remember, however, that genes merely represent the blueprint to uncover genetic
variants in common diseases, and they will not provide “the answer” to the question “What causes
glaucoma?” Considerable strides are needed to fully understand factors that affect gene expression, such
as DNA methylation, gene repair, copy-number variation, and telomerase action. In addition, proteomics
is arguably just as crucial to genomics when looking at normal physiology and disease. For instance,
posttranslational modifications, such as glycosylation, adenosine diphosphate- ribosylation, and
phosphorylation, that affect cell function may also contribute to differences in an individual's disease
manifestation and response to treatment.
Pharmacogenomic studies could reveal genetic factors that predispose to poor IOP response (Fig. 8.6) as
well as to higher-than-average risk for an adverse response—for example, the development of elevated
IOP in response to corticosteroid therapy.
The new challenges of genomics, and for the expected technological advances with proteomics and
metabolomics, are to determine whether we can predict disease risk, disease progression, and treatment
outcome. Despite the intricate biological and physiologic interactions among expression of drug target
genes, drug-metabolizing enzymes, and disease genes, an approach to identify genetic markers of “poor
IOP responders” has the potential to target patients with disease to more appropriate treatment, such as
surgery, to lower IOP more effectively, thus minimizing progressive optic nerve damage and visual field
loss.
The promise of personalized medicine is new abilities to improve on clinical decision making regarding
individualized treatment regimens based on the patient's genetic profile. It is equally as important to
consider health behaviors—that is, adherence with treatments—while conducting appropriately designed
studies. Lifestyle factors, such as diet, exercise, cigarette smoking, and alcohol use, are all included in
the individual health behaviors but have not been extensively studied for glaucoma. The genetic profile
would enable the assessment of risk for disease, protective genetic factors, disease progression, and
variations in treatment responses of both efficacy and toxicity.
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Figure 8.6 Variations in IOP response to glaucoma medical therapy are determined by pharmacokinetic
and pharmacodynamic processes (blue arrow) and interaction with the environment, disease, and
pathophysiologic processes. The sequence variants among pharmacokinetic and pharmacodynamic
genes are predicted to have functional consequences that contribute to the genetic component of
variance in IOP response. (Modified from pharmgkb.org, with permission of PharmGKB and Stanford
University.)
Revisiting Case 3
Our current knowledge can only begin to answer the patient's question. As our understanding grows
about applying genomic results to this potentially blinding disease, clinicians will be expected to be
informed about treatments that can be personalized for their patients. These treatments will be based on
a patient's genetic profile and will incorporate information on disease risk, disease progression, and the
likelihood of individual drug safety and efficacy.
Privacy and Counseling
The fear of genetic discrimination has presented an impediment to the widespread application of
personalized medicine. Legislation to protect patients against this risk is essential. An example is the
Genetic Information Nondiscrimination Act (GINA), was signed into law in the United States and which
offers protection against discrimination based on genetic information when it comes to health insurance
and employment (29).
As more widespread genetic testing becomes available, clinicians will need to safeguard these data and
also ensure that appropriate genetic counseling is available. The role of the counselor is to be an
informer, not an advisor. It will be important to provide the necessary facts and options, so that an
informed decision can be made by the patient and his or her caregivers.
Concluding Remarks
Personalized medicine will become a reality through identification of disease and pharmacogenetic
markers followed by careful study of how to employ this information for improving
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treatment outcomes. With advances in genomic technologies, research has shifted from the simple
monogenic disease model to a complex multigenic and environmental disease model. Our challenges lie
in developing risk models incorporating genegene interactions, gene copy-number variations,
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environmental interactions, treatment effects, and clinical covariates.
Future approaches to glaucoma therapeutics encompass identification of genetic markers for “non-IOP
responders”; problematic wound healing, which affects surgical outcomes; and incorporation of the
utility of growth factors, stem cells, and other non-pressure-based mechanisms to decrease glaucoma
neuropathy.
KEY POINTS
Genetic studies have the ability to
identify risk alleles for disease and predict the chance of developing disease,
identify genetic modifiers of age of onset,
identify genetic modifiers for disease progression,
identify genetic markers of treatment response to glaucoma medications, and
assist with disease classification.
The glaucomas are a complex group of diseases with considerable genetic heterogeneity. Genetic
variations have been found that cause glaucoma or are associated with syndromes that include
glaucoma, and loci have been identified that affect an individual's potential susceptibility to
glaucoma.
There are a large number of mapped locations for COAG, and three genes have been identified
(MYOC, OPTN, and WDR36). However, the vast majority of the genetic contribution to this form
of glaucoma and angle-closure glaucoma remains to be determined.
The identification of CYP1B1 gene for PCG, responsible for up to half of cases, is a major
improvement in our understanding of this devastating disorder.
Future studies in humans will provide an opportunity to correlate genotype to phenotype, while
animal studies will continue to unravel the complexity of biochemical networks that cause
glaucoma in its various manifestations. This may enable earlier detection, a better understanding
of the pathophysiology, and thus natural history of disease, and eventually the institution of more
rational, targeted therapy.
Given the five different main classes of drugs for glaucoma therapy, it is important to recognize
that genetic variability among the pharmacokinetic and pharmacodynamic pathways may
influence responses to these drugs.
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4. Stone EM, Fingert JH, Alward WL, et al. Identification of a gene that causes primary open angle
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5. Sud A, Del Bono EA, Haines JL, et al. Fine mapping of the GLC1K juvenile primary open-angle
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6. Damji KF, Song X, Gupta SK, et al. Childhood-onset primary open angle glaucoma in a Canadian
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7. Inagaki Y, Mashima Y, Fuse N, et al. Polymorphism of beta-adrenergic receptors and susceptibility to
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polymorphisms in the OPA1 gene. Hum Genet. 2002;110:52-56.
10. Copin B, Brezin A P, Valtot F, et al. Apolipoprotein E-promoter single-nucleotide polymorphisms
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24. Lynch S, Yanagi G, DelBono E, et al. DNA sequence variants in the tyrosinase-related protein 1
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in Caucasian Australians but with markedly lower penetrance than in Nordic people. Hum Mol Genet.
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Say thanks please
9 - Clinical Epidemiology of Glaucoma
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> Table of Contents > SECTION II - The Clinical Forms of Glaucoma > 9 - Clinical Epidemiology of
Glaucoma
9
Clinical Epidemiology of Glaucoma
Glaucoma affects more than 67 million persons worldwide, of whom about 10%, or 6.6 million, are
estimated to be blind (1). Glaucoma is the leading cause of irreversible blindness worldwide and is
second only to cataracts as the most common cause of blindness overall (1). Glaucoma is responsible for
14% of all blindness (2). In the United States, chronic open-angle glaucoma (COAG) affects more than
2.2 million persons, and this number is projected to increase to 3.4 million by 2020 (3). Over the same
time period in the developing world, the prevalence of glaucoma is expected to rise even more
dramatically as the population of adults older than 60 years more than doubles (2).
The social and economic impact of glaucoma is enormous but difficult to quantify. Economic data on
the cost of glaucoma are also limited. The total direct cost per case of treating newly diagnosed COAG
or ocular hypertension for 2 years was estimated to average $2109 in the United States and $2160 in
Sweden in 1998 (4). Costs have been shown to be greater for more advanced cases and uncontrolled
disease and to increase following trabeculectomy (5, 6). The annual direct costs of glaucoma and ocular
hypertension in the United States were estimated at $3.9 billion in 2001 (7); a separate estimate from
1991 put the direct costs of glaucoma (excluding ocular hypertension) at $1.9 billion (8). National per
capita estimates are similar for Canada but lower for Sweden and the United Kingdom (5, 9, 10).
FUNCTIONAL LIMITATIONS ASSOCIATED WITH GLAUCOMATOUS VISION LOSS
From the perspective of those whose visual function has been severely affected by glaucoma, the impact
of the disease can be profound and may include difficulty with reading and writing, activities of daily
living (cooking and eating, dressing and bathing, medication management, money management),
mobility with increased risk of falls, ability to drive, vocational challenges, social isolation, and
depression (11, 12, 13, 14, 15 and 16). As individuals age, the impact of visual dysfunction can be
amplified if comorbidities are present. These include hearing loss, arthritis, head tremors, and cognitive
impairment. The impact of glaucoma can be quantified by using various vision-targeted and generic
health-related quality-of-life measures, but is difficult to predict on the basis of visual function
measurements alone. Many factors such as physical health, psychological state, visual demands of daily
living, values, adaptability, and social and cultural milieu shape the changing impact of glaucoma on
individuals (17). This may explain in part the low correlation between visual field loss in glaucoma and
vision-targeted and generic measurements of health-related quality of life (18, 19). Vision-targeted
measures of health-related quality of life have found lower scores in glaucoma suspects than in healthy
controls and have been successively lower in those with early and moderate and advanced visual field
changes (20, 21, 22, 23 and 24); general health-related quality-oflife scores also have been shown to be
decreased in persons with glaucoma (20, 21 and 22, 25). In general, these findings support the notion
that glaucoma, as the ‘sneak thief’ of vision, causes subtle symptoms and modestly affects health-related
quality of life until the disease is advanced. Interestingly, visual changes associated with glaucoma are
often not interpreted as symptoms of a visual problem until after a diagnosis has been made (17). An
important consideration in the treatment of glaucoma is that therapy can itself adversely affect quality of
life (26, 27). Therapies may be inconvenient or expensive, cause discomfort, or lead to significant ocular
and systemic complications.
It has been suggested that strategies aimed at improving an individual's function be tied to socially
meaningful outcomes (28). Examples include maintaining functional independence; sustaining
meaningful relationships; enhancing one's psychosocial well-being; and being able to access
transportation, pursue leisurely activities, and maintain employment and economic productivity.
PREVALENCE, INCIDENCE, AND GEOGRAPHIC DISTRIBUTION OF GLAUCOMA
The prevalence of glaucoma has been studied extensively (Table 9.1), but the case definition of
glaucoma has varied widely and clinical classification has been inconsistent among studies (52).
Intraocular pressure (IOP), the appearance of the optic nerve head, and visual field abnormalities have
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all been used in varying combinations to define glaucoma; the status of the iridocorneal angle and the
presence or absence of secondary causes are typically used to determine the clinical classification of
glaucoma. These differences make it difficult to directly compare the prevalence findings of different
studies. There is, however, growing acceptance of the concept that glaucoma is a progressive optic
neuropathy characterized by a typical damage to the optic nerve head (cupping) and associated visual
dysfunction. Glaucomatous damage to the optic nerve appears to be the final common pathway to a
diverse assortment of etiologic factors and clinical subtypes.
There is some discussion in the literature about the value of distinguishing between normal-tension
glaucoma and
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COAG on the basis of IOP at presentation. In population-based studies, normal-tension glaucoma has
been far more common than expected, accounting for between 40% and 75% of individuals with newly
diagnosed COAG based on screening IOP (44, 50, 53). These entities are likely part of a spectrum of
disease in which IOP plays an important role, and other factors such as vascular, apoptotic, or
connective tissue factors are increasingly important at lower IOP levels (54); they less likely represent
distinct varieties of glaucoma.
Table 9.1 Prevalence of Glaucoma in Selected Population-Based Studies
Racial/Ethnic Group and
Age-Group, Participants, n Prevalence, by Type of Glaucoma,
a
y
%
Location
Any COAG
ACG
SG
Black
Baltimore, USA, 1991 (29)
>40
2396
4.7
4.7
_b
_b
Barbados, 1994(30)
40-84
4709
6.6
6.6
_b
_b
Kongwa, Tanzania, 2000(31)
>40
3268
4.2
3.1
0.6
0.5
b
St. Lucia, 1989(32)
30-86
1679
8.8
8.8
_
_b
Temba, South Africa, 2003 (33)
>40
839
53
2.9
0.5
2.0
Hispanic
Arizona, USA, 2001 (34)
>40
4774
2.1
2.0
0.1
_b
Asian
Alaska, USA, 1987(35)
>40
1923
2.7
2.7
_b
_b
Andhra Pradesh, India, 2000 (36, >40
1399
3.7
2.6
1.1
0.1
37)
Japan, 1991 (38)
>40
8126
3.5
2.6
0.3
0.6
Hovsgol, Mongolia, 1996(39)
>40
1000
2.2
0.5
1.4
0.3
Singapore, 2000 (40)
40-79
1717
4.7
2.4
1.5
0.8
Tamil Nadu, India, 2003 (41)
>40
5150
2.5
1.7
0.5
0.3
White
Baltimore, USA, 1991 (29)
>40
2913
1.3
1.3
_b
_b
Beaver Dam, USA, 1992(42)
43-84
4926
2.1
2.1
_b
_b
Bedford, UK, 1968(43)
>30
5941
0.9
0.7
0.2
_b
Blue Mountains, Australia, 1996 >49
3654
3.5
3
0.3
0.2
(44)
Egna-Neumarket, Italy, 1998(45) >40
5816
2.1
1.4
0.6
0.1
b
Framingham, USA, 1977(46)
52-85
2477
1.2
1.2
_
_b
Melbourne, Australia, 1998(47)
40-98
3271
2.0
1.7
0.1
0.2
Rhonda Valley, UK, 1966(48)
40-74
4231
0.7
0.3
0.1
0.3
b
Roscommon, Ireland, 1993(49)
>50
2186
1.9
1.9
_
_b
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Rotterdam, Netherlands, 1994(50) >55
Reykjavik, Iceland, 2003 (51)
>50
a Numbers
b Data on
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3062
1045
3.1
4.0
3.1
4.0
_b
_b
_b
_b
in parentheses are reference numbers.
glaucoma subtypes incomplete.
ACG, angle-closure glaucoma; COAG, chronic open-angle glaucoma; SG, secondary glaucoma.
The prevalence of open-angle glaucoma varies greatly among racial and ethnic groups (Table 9.1). In
the Baltimore Eye Survey, the prevalence of COAG in persons 40 years and older was found to be
significantly higher among blacks than whites (4.7% vs. 1.3%). Hispanics in the United States have been
found to have a prevalence of 2.0% for those 40 years of age and older, similar to findings of other
studies for whites in the same age range. The prevalence of COAG in Asian populations varies widely,
with many populations having similar prevalence levels to whites (Chinese in Singapore, 2.4%;
Japanese, 2.6%; Indians in Tamil Nadu, 1.7%), whereas other populations (Mongolian, 0.5%; Alaskan
Inuit, 0.1%) appear to have rates that are considerably lower. This summary is limited by differences in
definitions and classifications of glaucoma and different age distributions. However, the variation in the
prevalence of COAG in blacks and angle-closure glaucoma and COAG in Asians probably also reflects
the wide genetic heterogeneity within these broad racial and ethnic categories (55).
Age has an even more powerful influence on the prevalence of COAG than racial and ethnic grouping
does (Fig. 9.1 and Table 9.2). The age-specific prevalence of COAG (by race) is a useful starting point
for clinicians to estimate the probability of COAG when beginning an initial assessment. COAG is
uncommon before 40 years of age. In a pooled analysis of populationbased surveys, the prevalence of
COAG in whites increased from
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0.6% for age 40 to 49 years to 1.5% for 50 to 59 years, to 2.7% for 60 to 69 years, to 5.1% for 70 to 79
years, and finally to 7.3% in the 80 years and older age-group, a greater than 10-fold increase from the
40- to 49-year age-group (Table 9.2) (3). In the Baltimore Eye Survey, the prevalence of COAG among
blacks in the same survey was threefold to fourfold higher than in whites at almost every age interval
(Table 9.2). In U.S. Hispanics, the age-specific prevalence of COAG was similar to that of whites but
was significantly higher in the oldest age-group, equaling or exceeding the prevalence observed in
blacks. Similar to overall prevalence, the age-specific prevalence of COAG in some Asian populations
(in Tamil Nadu, India; Chinese in Singapore) is similar to that in whites, whereas in others (in
Mongolia), it appears to be considerably lower. In almost all of these studies, roughly a 10-fold increase
in prevalence occurs between the 40-to 49-year-old age-group and the oldest age bracket.
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Figure 9.1Age-specific prevalence of COAG from selected surveys. Data are from the Eye Diseases
Prevalence Research Group, Aravind Comprehensive Eye Survey, Baltimore Eye Survey, and Proyecto
VER.
Another useful clinical perspective on the geographic distribution of glaucoma is the relative frequency
of COAG, angle-closure glaucoma, and secondary glaucoma in different populations. In black and white
populations, COAG usually accounts for 85% to 90% of all glaucomas. In contrast, angle- closure
glaucoma predominates in some Asian populations, such as in Mongolia, where it accounts for 64% of
glaucoma cases. Angle-closure glaucoma has been estimated to account for half of all cases of glaucoma
worldwide (1). In other Asian populations, angle-closure glaucoma is less common than COAG, such as
in a Chinese population in Singapore (angleclosure glaucoma, 32%; COAG, 42%) and an Indian
population in Tamil Nadu (angle-closure glaucoma, 19%; COAG, 65%), whereas among Japanese
patients, angle-closure glaucoma accounts for 9% of glaucoma, similar to rates in whites. It is easy to
see how profoundly geographic location and the population being treated may affect an
ophthalmologist's perspective on glaucoma. Secondary forms of glaucoma collectively account for
between 5% and 20% of glaucoma cases in studies where this is specified (Table 9.1).
table 9.2 Prevalence of Chronic Open-Angle Glaucoma (COAG), by Age, According to
Race/Ethnicity and Study Locationa
Age-Group
Prevalence of COAG, %
White
Black
Hispanic
Indian
United States
Baltimore
Baltimore
Arizona
Tamil Nadu
40-49 y
0.6
0.9
1.2
0.5
0.3
50-59 y
1.5
0.4
4.1
0.6
1.6
60-69 y
2.7
0.9
5.5
1.7
1.8
70-79 y
5.1
2.9
9.2
5.7
2.9
>80 y
7.3
22
11.3
12.6
All
1.3
4.7
2
1.2
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aStudy
sources, by location: USA—Eye Diseases Prevalence Research Group (3); Baltimore (USA)—
Baltimore Eye Survey (29); Arizona (USA)—Proyecto VER (34); Tamil Nadu (India)—Aravind
Comprehensive Eye Survey (41).
Whereas the prevalence of glaucoma is the proportion of a population with the disease at a given time
point, incidence is the rate at which new cases occur during a specified period. The incidence of
glaucoma is also strongly influenced by age and race. For the clinician, incidence serves as a point of
reference to estimate the risk for glaucoma over a period of time (Table 9.3). The best estimates of the
incidence of glaucoma come from a handful of population-based cohort studies (56, 57 and 58). In the
Melbourne Visual Impairment Project, the overall incidence of open-angle glaucoma in whites aged 40
years and older was 0.5% over 5 years, or roughly 1/1000 per year; in blacks of the same age in the
Barbados Eye Study, the incidence was 2.2% over 4 years, or about 5.5/1000 per year. In both
populations, the incidence increased steadily with age (Table 9.3). This comparison also suggests that
the incidence of COAG in blacks increases at an earlier age than in whites and is much greater than in
whites in the fourth and fifth decades of life, but is similar in the oldest age-group (80 years or older).
However, differences in how progression was determined in these studies mean that direct comparisons
may not be valid (59, 60).
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Table 9.3Incidence of Chronic Open-Angle (COAG), by Age, According to Race/Ethnicity, Study
Location, and Incidence Periodaa
Age-Group
Incidence of COAG, %
White
Black
Australia
Sweden
Barbados
5y
1y
1y
4y
1y
40-49 y
0
_
_
1.2
0.3
50-59 y
0.1
0.02
_
1.5
0.38
60-69 y
0.6
0.12
_
3.2
0.8
70-79 y
1.4
0.28
_
_
_
=80y
4.1
0.82
_
4.2
1.05
All
0.5
0.1
0.24
2.2
0.55
aStudy sources, by location: Melbourne, Australia—Melbourne Visual Impairment Project (VIP) (56);
Dalby, Sweden—(57); Barbados—Barbados Eye Studies (58).
Several clinical trials have reported the risk of progression of established COAG without treatment.
These estimates offer a benchmark to clinicians and patients against which to weigh the risks of
treatment, bearing in mind that progression rates may vary widely depending on how progression is
determined (59, 60). In the Early Manifest Glaucoma Trial (EMGT), the rate of progression at 6 years
was 62% without treatment and was decreased to 45%, with an average IOP lowering of 25%, with
treatment (61, 62). The Collaborative Normal Tension Glaucoma Study (CNTGS) followed a group with
more advanced glaucoma and lower IOPs and observed progression in 60% at 5 years without treatment
(63). This percentage fell to 20% with treatment targeting greater than 30% IOP lowering.
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Figure 9.2Natural history of COAG. Schematic depiction of the natural history of COAG showing loss
of axons over time for selected patients with glaucoma, a: An individual without glaucoma, b:
Subthreshold axonal loss from glaucoma that does not progress beyond the suspect category, c: Axonal
loss from glaucoma that responds to treatment (*) compared with d, glaucoma that remains untreated
because of a delay in diagnosis, e: Aggressive axonal loss from glaucoma that is detected only after the
onset of symptoms and progresses to blindness despite treatment (**). The phases of chronic disease and
clinical stages of glaucoma with fields and disc findings have been added to the graph along the left and
right margins. The optic nerve drawings depict typical neural rim changes of glaucoma in a patient with
a baseline cup-to-disc ratio of 0.5 before axonal loss; patients with a larger or smaller cup-to-disc ratio at
baseline would have different neural rim findings at intermediate stages but would converge in advanced
disease.
NATURAL HISTORY OF GLAUCOMA
The natural history of COAG can be divided into three phases of chronic disease to illustrate several
important concepts relevant to clinical care (Fig. 9.2).
The first of these phases is called the latency phase. It begins with the onset of glaucomatous optic nerve
damage and extends up to the detection threshold. The etiology of glaucomatous optic nerve damage is
not well understood but is thought to result from a disturbance in the delicate balance of vascular,
connective tissue, mechanical, and neural components that keep the optic nerve head healthy and
functioning. An imbalance such as a rise in IOP and increased pressure gradient across the optic nerve
head may, in some individuals, be intolerable to some axons and lead to cell death by apoptosis (64).
However, many individuals with elevated IOP do not have glaucoma, and many persons with glaucoma
have non elevated IOP (53). Clearly, other factors are also involved in glaucomatous optic nerve
damage, and evidence continues to build in support
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of vascular tissue, connective tissue, and neural causes, including variations in cerebrospinal fluid (CSF)
pressure (see Chapter 4). It appears that low-level axonal loss may occur with aging in healthy
individuals (65, 66, 67 and 68), but it is unclear how this relates to glaucomatous optic nerve damage.
The detection threshold for glaucoma is defined as the point at which glaucomatous optic nerve damage
can be accurately detected by diagnostic testing. This marks the beginning of the lengthy asymptomatic
phase during which glaucoma is detectable, the so-called detectable preclinical phase that continues until
glaucomatous optic nerve damage leads to symptoms. The detection of early glaucomatous optic nerve
damage is challenging. In terms of visual field testing, considerable glaucomatous optic nerve damage
can occur before the threshold of detection is reached. It has been reported that up to 40% of axons can
be lost before white-on-white Humphrey perimetry will show an abnormality (69, 70), a finding
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supported by subsequent experimental studies in monkeys (71) (Fig. 9.3). Tests such as the frequency
doubling technology and short-wavelength automated perimetry (SWAP) maybe able to detect
glaucomatous optic nerve damage before conventional white-on-white perimetry can, but they may have
similar inherent psychophysical limitations. The detection of early glaucomatous optic nerve damage by
optic nerve examination at a single visit is also difficult, but for different reasons, there is a large overlap
between the appearance of healthy and glaucomatous optic nerves. Nerve fiber layer imaging techniques
are helpful in distinguishing some normal variants from glaucomatous optic nerve damage. Careful
documentation of optic nerve appearance, preferably by using stereoscopic disc photography or another
form of imaging, permits earlier diagnosis and earlier detection of progression by allowing detection of
subtle changes from glaucomatous optic nerve damage on subsequent assessments that would otherwise
be missed (see Chapter 4).
Figure 9.3 Loss of visual sensitivity as a function of loss of ganglion cells caused by experimental
glaucoma in macaque monkeys, compared with the contralateral control eye. Mean values (± standard
deviation [bars]) are shown for each of seven levels of ganglion cell loss with a fitted curve. Visual field
defects greater than 15 dB are almost always caused by ganglion cel losses of more than 70% (71).
Finally, the clinical phase begins with the onset of symptoms; in COAG, this seldom occurs before the
disease is advanced. However, chronic glaucoma is generally slowly progressive and may never reach
this stage or may take decades to do so. As a result of the lengthy asymptomatic phase, glaucoma is
often diagnosed in the course of periodic eye examinations before the clinical phase, but many cases are
not. COAG may also behave aggressively and become symptomatic within several years of presumed
onset. Ultimately, some patients with chronic glaucoma eventually go blind.
The natural histories of a patient with a healthy optic nerve and four other patients with COAG are
shown in Figure 9.2. Using a ‘rule of tens,’ we can roughly approximate the distribution of a white or
black population into the categories of COAG shown in this figure. For every 1000 persons aged 40
years and older, 100 are suspected of having COAG on the basis of field, disc, IOP findings, or dense
risk factors; 10 have COAG, and approximately 1 will be blind as a result of COAG.
CLINICAL RISK FACTORS FOR CHRONIC OPEN-ANGLE GLAUCOMA
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Risk factors are clinically useful to assess the risk for glaucoma based on the characteristics of the
individual patient. To use this knowledge most effectively, it is helpful to understand the relative
importance and magnitude of clinical risk factors. Although many risk factors have been identified for
COAG, a much smaller number is well supported by evidence. Most of the evidence for COAG risk
factors has been obtained from prevalence surveys or case-control studies. These have been
complemented, especially in recent years, by high-quality clinical trials and cohort studies. In general,
there is good agreement on risk-factor information based on prevalence and that based on incidence.
Some risk factors for COAG are also risk factors for progression. Clinical risk factors may be divided
into general risk factors, ocular risk factors, and systemic risk factors. (Risk factors for the conversion of
suspected glaucoma with elevated IOP to COAG are discussed in Chapter 10.)
General Risk Factors
Age
As described previously, population-based studies of prevalence and incidence consistently show a
steady rise in rates with increasing age. As a rule of thumb, prevalence tends to roughly double for each
decade over 40 (i.e., relative risk [RR] of 2 per decade) and is about 10-fold higher in the 80 years and
older group compared with the 40- to 49-year-old group (Table 9.2). In blacks, the RRs for incidence by
decade are lower than in whites (because of the higher incidence seen in the 40- to 49- year-old
reference group) (Table 9.3). In the EMGT, the RR of progression of early glaucoma was 1.5 for those
68 years of age and older, compared with younger persons (72).
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Race
In general, the prevalence of COAG is highest in black populations; intermediate in whites, Hispanics,
and southern Asian populations (Singapore Chinese, Indian); and lowest in northern Asian populations
(Mongolia, Inuit) (Table 9.1). The Baltimore Eye Survey found the prevalence of COAG in blacks to be
four times greater than that in whites (29). A similar difference in the overall incidence of COAG for
those aged 40 years and older has been observed between recent population-based cohorts of blacks and
whites (56, 73) (Table 9.3). In the Advanced Glaucoma Intervention Study (AGIS) (74), black race was
not shown to be a risk factor for progression, in contrast to an earlier cohort study (75). In the CNTGS
(76), Chinese patients had a significantly lower risk of progression than white patients.
Family History
A family history of COAG is an important risk factor for COAG. Having a first-degree relative (parent,
sibling, or child) with glaucoma has been consistently associated with an increased risk for COAG in
prevalence surveys (77, 78, 79, 80 and 81). The odds ratio (OR) of COAG for a family history of
glaucoma is higher if based on patients with previously diagnosed glaucoma (Baltimore OR, 4.7; Blue
Mountains Eye Study OR, 4.2) than if based on newly detected cases (Baltimore OR, 2.8; Blue
Mountain Eye Study OR, 2.4). This suggests that having a diagnosis of COAG leads to a greater
awareness of glaucoma in the family. The association between COAG and family history may be
stronger when the affected relative is a sibling (OR, 3.7) rather than a parent (OR, 2.2) or child (OR, 1.1)
(78). In one population-based survey, researchers directly examined 497 siblings and offspring of
patients with glaucoma and of control participants (80). For first-degree relatives of patients with
definite glaucoma, the estimated lifetime RR for glaucoma was 9.2, albeit with very wide confidence
intervals (CIs) (95% CI, 1.2 to 73.9). Family history was a risk factor for glaucoma in one prospective
population-based study (RR, 2.1) (82), although no such association was found in the Ocular
Hypertension Treatment Study (OHTS). In prospective studies of established glaucoma, family history
has not been shown to be a significant predictor of progression (72, 76).
Table 9.4 Intraocular Pressure (IOP) and the Rates of and Relative Risk I for Chronic OpenAngle Glaucoma, by Study
a
Baltimore Eye Survey
Barbados Eye Studyb
IOP Level, min Prevalence, Relative Relative
IOP Level, mm 4-Year Incidence, Relative
hg
%
Risk
HG
%
Risk
2011/10/19
<15
0.7
1.0
<17
16-18
1.3
2.0
>17-19
19-21
1.8
2.8
>19-21
22-24
8.3
12.8
>21-23
25-29
8.3
12.8
>23-25
30-34
25.4
39
>25
=35
26.1
40.1
a Data shown are for black and white participants combined (53).
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0.7
1.1
2.7
3.6
6.9
18.3
1.0
1.6
4.0
4.8
10.5
24.7
b Estimates
adjusted for age, sex, hypertension, and IOP lowering (58).
Ocular Risk Factors
Intraocular Pressure
The evidence that IOP is a risk factor for glaucoma has recently become so strong that, unlike any other
risk factor for glaucoma, it satisfies criteria commonly used to assess causality (83, 84). A strong doseresponse relationship between IOP and glaucoma has consistently been shown in prevalence surveys
(Table 9.1) and in longitudinal studies of incidence and progression (73, 82, 85, 86). The most decisive
new evidence in recent years was the finding in randomized clinical trials that IOP lowering decreased
the incidence and progression of glaucoma compared with no treatment (61, 63, 85). In addition, there is
support for plausible biologic mechanisms that link elevated IOP to apoptosis of ganglion cell neurons
through blockage of retrograde axonal transport (87, 88). In short, IOP is best considered both a risk
factor for and a cause of glaucoma. A good analogy is the relationship between smoking and lung
cancer, in which smoking is both a strong risk factor for lung cancer and one of several causes.
In the Baltimore Eye Survey, the prevalence of COAG rose with increasing IOP (Table 9.4). The
prevalence of COAG in persons with an IOP of 35 mm Hg or greater was more than 40 times as high as
that in persons with an IOP less than 15 mm Hg. The incidence of COAG was found to increase steadily
with IOP in the Barbados Eye Study to an RR of 25 for an IOP of more than 25 mm Hg, compared with
a reference group with an IOP less than 17 mm Hg (Table 9.4). In the population of the Melbourne
Visual Impairment Project, it was estimated that for every 1 mm Hg, the risk for glaucoma increased by
10%. Importantly, the OHTS also demonstrated that reducing the IOP by an average of 23% decreased
the incidence of COAG by 60% (85). In the EMGT and the CNTGS, an IOP reduction of 25% and
greater than 30% cut the risk of progression by 33% and 50%, respectively, compared with no treatment
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(61, 63). Other clinical trials of COAG report that greater pressure lowering results in less progression
(86, 89, 90).
An important implication of these population-based data and the CNTGS findings is that IOP may
contribute to the onset of glaucoma even in patients with untreated IOP in the low-normal range and that
some of these patients will benefit from IOP reduction. An intriguing finding from AGIS was that
persons with the greatest IOP reduction (mean IOP, 12.3mm Hg with treatment vs. 23.3 mm Hg before
treatment) had stable visual fields (based on mean field defect score; risk of progression in the group
was 14.4%) in contrast to groups with higher levels of IOP that showed progressive field loss over the 8year follow-up period (86). This suggests that, at least in hypertensive COAG, an IOP level exists below
which progression of glaucoma is stopped or at least suppressed to subclinical levels in most patients.
High diurnal variation in IOP may also be a risk factor for progression in addition to the risk related to
mean IOP.
Optic Nerve Head and Peripapillary Features
When the parameters used to define glaucoma, such as cup-todisc ratio, are also treated as risk factors, a
problem with circular reasoning may result. One population-based study reported that the incidence of
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COAG for persons with a baseline cupto- disc ratio of more than 0.7 was 8.6-fold higher than for those
with a cup-to-disc ratio of less than 0.7 (56). However, this estimate may be inflated because one of the
criteria for defining COAG was having a cup-to-disc ratio of more than 0.7. Another feature of the optic
nerve head that may be associated with glaucoma is the vertical disc diameter and the disc area (91, 92
and 93), possibly because of greater susceptibility to glaucomatous nerve damage (94, 95). However, the
reported associations may have occurred in part because larger discs have larger cup-to-disc ratios (96,
97, 98 and 99), which in turn were part of the diagnostic criteria in most of these studies.
Optic disc hemorrhages were first recognized as a precursor to glaucomatous optic nerve damage by
Bjerrum in 1889. This somehow fell out of clinical lore until it was rediscovered in 1977, when Drance
and colleagues provided the first longitudinal findings (100), subsequently confirmed by others (101,
102), that eyes with a disc hemorrhage had an elevated risk for progressive visual field loss (62, 103,
104). Additional support has been provided by both the EMGT (RR, 1.02 per percentage of visits with
disc hemorrhage present) and the CNTGS (RR, 2.72) (76). Population surveys that have specifically
reported on optic disc hemorrhage have found prevalences in adults ranging from 0.9% to 1.4%, of
which only 2% and 30%, respectively, were in persons with glaucoma (42, 105). In the second of these
two studies, the prevalence of glaucoma was found to be increased 10-fold in those with disc
hemorrhages, and disc hemorrhages were much more common in normal-tension glaucoma (25%) than
in high-tension glaucoma (8%) (105). Interestingly, in another population-based series of adults with
disc hemorrhages but without glaucoma on screening, 5 of 12 patients followed up for more than 6 years
developed visual field loss by year 7 (106). However, particularly in individuals with no other risk
factors for glaucoma, an optic disc hemorrhage may be due to other causes, including microvascular
disease from diabetes mellitus or hypertension or from a posterior vitreous detachment, Valsalva
maneuver, or anticoagulation.
Atrophy of the neurosensory retina and retinal pigment epithelium about the optic nerve head is known
as peripapillary atrophy and has been shown to correlate with the presence of glaucoma (96, 107, 108).
Peripapillary atrophy may also worsen along with glaucoma progression (109), although this has not
been a consistent finding. Zone alpha peripapillary atrophy has been found in 58% of a white population
older than 55 years, rendering it of little diagnostic value; zone beta peripapillary atrophy has been
reported to be three times as common in patients with COAG as in controls (96), but it is associated with
myopia and is also quite common, with a prevalence of 13%. Peripapillary atrophy does not appear to be
specific to glaucoma, and its role in the diagnosis and management of COAG remains unclear.
Myopia
An association between myopia, particularly high myopia, and open-angle glaucoma has long been
recognized and is supported by numerous case series and case-control studies (110, 111, 112, 113 and
114). This association is also supported by large population- based prevalence surveys that reported an
elevation of prevalence of COAG in those with any myopia of 48%, 60%, and 70% after adjustment for
age and sex (93, 115, 116 and 117). Another survey reported a twofold- to threefold-increased
prevalence of glaucoma in individuals with myopia (118). However, individuals with myopia were not
found to have a higher incidence or progression of glaucoma in the OHTS or the EMGT, respectively
(72). Other longitudinal studies have previously shown high myopia to be a risk factor for progression
(119, 120).
Other
In EMGT, having exfoliation syndrome and having a relatively thin central corneal thickness were
associated with an increased risk for progression (62).
Systemic Risk Factors
Diabetes Mellitus
The prevalence of COAG appears to be higher in the diabetic population by a factor of about 2 in the
majority of population-based surveys (121, 122, 123 and 124), although an association was not found in
others (125, 126). Most of these studies did not use IOP in their criteria for defining COAG, and one of
them showed that the association of diabetes and glaucoma persisted after adjustment for IOP (124).
Findings from numerous clinical studies on the association of diabetes and glaucoma are inconsistent
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and are subject to greater methodological limitations than population-based surveys, particularly
selection bias (127, 128). IOP is an important confounder of the association between diabetes and
glaucoma because persons with diabetes appear to have a slightly higher IOP and have been reported to
have a higher prevalence of ocular hypertension and incidence of IOP elevation, compared with persons
who do not have diabetes (72, 123, 124, 128). Diabetes has not yet been shown to
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increase the incidence of glaucoma. Although the weight of available evidence suggests that diabetes is
probably a risk factor for glaucoma, this has not been a consistent finding. Self- reported diabetes was
associated with COAG progression in the AGIS and the CIGTS (Collaborative Initial Glaucoma
Treatment Study) but not in the CNTGS or the EMGT (129).
Blood Pressure
The most meaningful blood pressure variable related to glaucoma appears to be diastolic ocular
perfusion pressure or the difference between diastolic arterial pressure and IOP. Diastolic ocular
perfusion pressure has consistently been associated with COAG in several large population-based
surveys that reported a severalfold increase in the prevalence of COAG among those with lower
perfusion pressures (128, 130). These surveys suggest that a steep increase in the prevalence of
glaucoma occurs when diastolic ocular perfusion pressure falls below 55 mm Hg. This is supported by a
large population-based cohort study that showed a strong dose-response gradient between the incidence
of glaucoma and diastolic perfusion pressure, with an RR for glaucoma of 3.2 for those with the lowest
diastolic perfusion pressure (<55 mm Hg) (73).
The literature on the association between systolic or diastolic blood pressure and glaucoma is confusing,
with some population-based studies showing an association and others not (46, 122, 128, 130, 131).
Similarly, some clinical studies on risk factors link higher blood pressures to glaucoma, and others
report that lower blood pressure is more common in those with COAG and those with progression of
glaucoma (114, 132, 133, 134, 135, 136, 137 and 138). The best evidence comes from a large
population-based cohort study that showed a 51%-decreased risk for COAG in persons with systolic
hypertension at baseline and that this protective effect was greater at higher levels of blood pressure
(73). One study also described an increased prevalence of glaucoma at both very low and very high
levels of systolic blood pressure, with the lowest prevalence in the midrange (130). It may be that high
and low blood pressures are linked to glaucomatous optic nerve damage by different mechanisms. This
may explain, in part, the apparently contradictory literature on the association between blood pressure
and glaucoma.
Lower blood pressure has been reported as a risk factor for progression of COAG in EMGT (129).
Numerous large surveys have consistently found that IOP elevation is associated with increased systolic
and diastolic blood pressure (122, 128, 130). However, the associated change in IOP is not clinically
significant. For example, in the Baltimore Eye Survey, a 10-mm Hg increase in systolic or diastolic
blood pressure was associated with an increase in IOP of 0.25 and 0.19 mm Hg, respectively (128).
There has been considerable attention paid to the role of episodic decreases in blood pressure in
glaucoma, particularly in normal-tension glaucoma. Nocturnal arterial hypotension, which has also been
implicated in anterior ischemic optic neuropathy, has been linked to the presence of COAG and
normaltension glaucoma and the progression of normal-tension glaucoma and COAG (137, 139, 140,
141, 142, 143 and 144). Several clinical studies also suggest that nocturnal arterial hypotension is more
common in normal-tension glaucoma than in COAG with elevated IOP (139, 145). There are several
reports of a hemodynamic crisis precipitating optic nerve damage in patients with COAG, but it has not
been shown to occur more frequently than in individuals without COAG (146, 147). Individuals with
glaucoma and diastolic perfusion pressures less than 55 mm Hg may be most at risk due to episodes of
decreased blood pressure, such as from nocturnal arterial hypotension, general anesthesia, and
overmedication for systemic hypertension; however, this remains to be established.
Migraine
Some evidence supports an association between migraine headaches and normal-tension glaucoma. Two
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case-control studies reported an association between a history of typical migraine headaches and
normal-tension glaucoma but not COAG with elevated IOP (148). A third case-control study had similar
findings for stringent definitions of migraine, but the results did not reach statistical significance. The
CNTGS found that a history of migraine increased the risk of progression by a factor of 2.6. Vasospasm
is thought to play a central role in the pathogenesis of migraine, and other studies have found a
predisposition to vasospasm in patients with normal-tension glaucoma (149, 150, 151, 152 and 153).
Although a fair and growing amount of evidence links normal-tension glaucoma with migraine or
vasospasm, this does not appear to be the case for all COAG in the general population, according to two
large, population-based studies (154, 155).
Cerebrospinal Fluid Pressure
A growing body of evidence suggests that lower CSF pressure may increase the risk for open-angle
glaucoma in a similar manner to elevated IOP (see Chapter 4). Studies show that patients with COAG
have lower CSF pressures, which increases translaminar pressure differences (156, 157). Conversely,
higher CSF pressures are found in persons with ocular hypertension, which would seemingly have the
opposite effect. In prospectively conducted research, Ren and coworkers found that blood pressure was
correlated with IOP and CSF pressure. Studying the role of CSF pressure in patients with glaucoma
presents unusual challenges but may help clarify the relationships among IOP, blood pressure, and the
risk for glaucoma.
Other Systemic Risk Factors
There is equivocal evidence linking several thyroid disorders to COAG. In two case series,
hypothyroidism was more common among patients with glaucoma than among persons without
glaucoma (158, 159), and treating hypothyroidism has been shown to lower IOP and increase outflow
facility (160). However, a case series of 100 consecutive patients with newly diagnosed hypothyroidism
detected no glaucoma and found no association between thyroid function and IOP (161). An older case
series also found no abnormalities in thyroid function in COAG (162). Graves disease has been
associated with an increased prevalence of ocular hypertension and glaucoma (163, 164), possibly
secondary to orbital changes and raised episcleral venous pressure.
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Other endocrine disorders have not been associated with COAG but may affect the IOP. Cushing
syndrome may lead to elevated IOP, which normalizes with control of the disease (165, 166). Pituitary
dysfunction may be associated with IOP fluctuations (167). Elevated levels of progesterone or estrogen
may lower eye pressure (168), whereas testosterone may raise it (167).
Sleep apnea is characterized by recurrent complete or partial upper airway obstruction during sleep,
leading to episodes of transient hypoxia. The condition is amenable to treatment and is typically seen in
overweight men with thickset necks, a history of loud snoring, and self-report of morning
hypersomnolence. Two case series have described a higher-than-expected prevalence of sleep apnea in
patients with COAG and normaltension glaucoma (169, 170).
Infectious and autoimmune risk factors have been associated with COAG (171, 172, 173 and 174).
COAG does not appear to be associated with elevated cholesterol or high-density lipoprotein level or
obesity (175, 176).
PROGNOSIS FOR BLINDNESS
Risk for Blindness from COAG
The primary goal of glaucoma treatment is to minimize the lifetime risk for significant loss of visionrelated quality of life due to glaucoma. However, there is limited information to help the clinician to
quantify the lifetime risk for blindness for a particular patient. One source of useful data comes from the
proportion of individuals with glaucoma who were bilaterally blind (from glaucoma) in populationbased surveys. This ranges from 2.5% to 6.2% in whites and appears to be higher in blacks, at 7.9% (29,
42, 49, 177). However, these figures include all individuals with glaucoma regardless of the duration of
disease and consequently underestimate the risk for blindness from glaucoma at the end of life.
Table 9.5 Long-Term Estimated Risk for Blindness Due to Chronic Open-Angle Glaucoma in
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Selected Studies
Study (Reference)
Type of Blindness Evaluated, and Timing
Risk for Blindness, %
and Description
Hattenhauer et al., 1998 (178)a
100 Patients followed up after receiving a diagnosis of Monocular, at 20 y after
COAG in 1965-1980
COAG diagnosis
Binocular, at 20 y after
COAG diagnosis
191 Patients followed up and treated for OHT after
Monocular, at 20 y after
diagnosis in 1965-1980
OHT diagnosis
OHT diagnosis
a,b
Chen, 2003(179)
186 Patients followed up at a glaucoma specialty clinic Monocular, at 15 y after
since receiving a diagnosis of COAG after 1975
COAG diagnosis
COAG diagnosis
Kwon et al., 2001 (180)
40 Eyes followed up at a glaucoma subspecialty clinic In study eye, at 22 y
after trabeculectomy surgery done in or after 1972
after surgery
a Study sample included persons with exfoliation.
54
22
14
4
15
6
19
b Study
sample included persons with pigment dispersion. COAG, chronic open-angle glaucoma; OHT,
ocular hypertension.
Outcomes from the long-term follow-up of cases are also helpful to estimate prognosis but must be used
with caution because of limitations with generalizing from these studies to current patient care. In a
community clinical practice in Olmstead County, Minnesota, the 20-year risk for blindness in
individuals with newly diagnosed open-angle glaucoma between 1965 and 1980 was 22% in both eyes
and 54% in one eye (178). In patients receiving treatment for ocular hypertension, the 20- year risk for
blindness was 4% in both eyes and 14% in one eye. A more recent clinical series of patients from a
subspecialty glaucoma clinic who received a diagnosis of COAG after 1975 showed a 15-year risk for
blindness due to glaucoma of 6.4% in both eyes and 14.6% in one eye (179) (Table 9.5). One of the
difficulties in using these findings is that a patient with newly diagnosed disease today would be
expected to do much better because of improvements in glaucoma care over the past three or four
decades. Perhaps, the greatest difficulty in applying these figures to the care of a particular patient is that
these clinical studies lump together newly diagnosed COAG of all levels of severity at the time of
diagnosis. Consequently, patients with early glaucoma should fare much better overall, whereas those
with advanced glaucoma should have an even poorer prognosis (Table 9.5).
Risk Factors for Blindness from COAG
Advanced Stage
Rough general estimates of prognosis in glaucoma can be refined somewhat by the presence or absence
of risk factors for glaucoma blindness, including advanced stage, young age, inadequate IOP control,
and ongoing progression. Not only are more advanced stages of glaucoma further along in the process
leading to blindness, but some evidence also suggests that more advanced glaucoma is more likely to
progress than earlier stages of the disease and may require greater IOP lowering to halt
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progression (181, 182, 183 and 184). However, other longitudinal studies have not found a more rapid
progression in those with worse initial visual field scores (101, 180, 185).
Young Age
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Onset of glaucoma at a younger age is another risk factor for blindness because the glaucoma is
expected to have longer to progress. The median estimated duration of COAG in the United States is 13
years in whites, with 25% of cases beginning by age 64 and 50% by age 72 (1). In blacks, the median
duration is estimated to be 16 years, with 25% of cases beginning by age 54 years and 50% by age 65
years (1). The onset of COAG before the median age of onset portends a longer duration of disease and
a higher lifetime risk for blindness than the median; the onset of COAG in the earliest 25th percentile
portends a considerably longer duration and higher level of risk. Furthermore, significant comorbidities
may curtail life expectancy. The earlier onset and longer duration of COAG in black patients, compared
with other patients, may largely account for the higher risk for glaucoma-related blindness among blacks
in the United States (1), although other factors, such as decreased access to health care, may contribute
(186, 187, 188, 189 and 190).
Inadequate Intraocular Pressure Control
It has long been standard clinical practice to treat glaucoma by safely lowering IOP below the level at
which optic nerve damage occurred. Recent clinical trials have conclusively shown that failure to do so
forfeits the benefit of IOP lowering and results in a higher risk of progression to blindness. Patient
nonadherence to glaucoma-treatment regimens is one cause of inadequate IOP lowering and has been
shown to increase the risk for blindness by a factor of 1.8 (179). Several studies have noted marked
differences in individual susceptibility to IOP and have stressed the importance of additional IOP
lowering in the face of ongoing progression (182, 191). This is supported by numerous studies showing
that greater IOP reduction results in less progression (86, 192, 193, 194, 195 and 196). However, in
blinding glaucoma, patients commonly progress to blindness despite IOP lowering to the mid to low
teens (179, 191). It may be that heightened susceptibility to IOP damage or non-IOP-dependent
mechanisms of damage may be more prominent in patients with blinding glaucoma, at least in the last
stages of the disease.
High Rate of Progression Despite Treatment
A high rate of progression despite treatment is itself another risk factor for glaucoma blindness. The rate
of visual field progression has been found to be 3 to 10 times more rapid in those eventually progressing
to blindness than in age- and initial field-matched controls, although the IOP was actually lowered
further in those progressing to blindness (191). Clinically, time to definite progression is often used as a
practical indicator of progression rate. As one reference point, the median time to definite progression in
treated COAG (mean initial IOP, 15.5 mm Hg after 25% IOP reduction) was about 6 years in the EMGT
with the simple endpoint of significant progression of the same three or more points on a glaucoma
change probability map (Humphrey 24-2) on three consecutive fields. However, even patients who take
this long to show definite progression may eventually be blinded by glaucoma if they have advanced
glaucoma; also, even slow progression may eventually lead to blindness in those with a long life
expectancy or whose progression accelerates. COAG is often an asymmetric disease, and an aggressive
clinical course in one eye may foreshadow the clinical course of the fellow eye (182, 197, 198). A strong
family history of aggressive COAG may also put a patient at higher risk for significant vision loss.
Prognosis for Blindness for Angle-Closure and Secondary Glaucomas
Although the foregoing discussion on risk factors for blindness in glaucoma relates to COAG, most of
the risk factors discussed also apply to angle-closure glaucoma and secondary glaucoma. Prevalence
surveys suggest that blindness is more common with angle-closure glaucoma and secondary glaucoma
than with COAG. In cases of angle-closure glaucoma, estimates of glaucoma blindness in at least one
eye range from 10% to 50% in Inuit and Chinese patients, and bilateral blindness in angleclosure
glaucoma has been reported in 21% of cases in blacks in East Africa (31, 35, 40, 199). The
corresponding figures for secondary glaucoma (neovascular, lens related, posttraumatic, and uveitic)
with blindness in at least one eye were 71% in Chinese patients and for bilateral blindness were 25% in
East Africans (31, 40). In each setting, the estimates given were higher than those for blindness due to
COAG.
Undiagnosed Glaucoma
Prevalence surveys in primarily white populations from established market economies have consistently
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shown that about 50% of cases of COAG in the population had not yet been diagnosed (46, 47, 49, 200).
Among Chinese patients in Singapore, this percentage is 91% for COAG but only 29% for angle-closure
glaucoma (40), presumably because the clinical course of angle-closure glaucoma is more likely to
cause symptoms. Diagnosis of glaucoma has been found to be more likely in those with a history of
other eye disease, a first-degree family history of glaucoma, and the use of one or more general
medications.
A number of lines of evidence suggest that it is not just early glaucoma that is undiagnosed in the
population. A series of 220 consecutive cases of newly diagnosed glaucoma from a hospital-based
ophthalmology clinic in the United Kingdom reported that 50% had a visual field defect within 5
degrees of fixation (201, 202). Among patients with newly diagnosed COAG, between 6% and 10%
were reported to be blind in at least one eye (178). In addition, 45% of new cases of glaucoma blindness
registered on the Massachusetts Blindness registry between 1970 and 1980 were blind due to glaucoma
in one or both eyes at the time of their glaucoma diagnosis, similar to earlier reports from the United
Kingdom (203, 204). Risk factors for late presentation include lower socioeconomic status and time
since last ocular examination (201).
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Missed Opportunities for Diagnosing Glaucoma
Although delayed diagnosis may be due to a lack of ocular assessment, missed opportunities for
diagnosis may also play an important role. In Sweden, a 5-year program ending in 1997 screened for
glaucoma by using tonometry and fundus photography as an initial examination and identified 402 cases
of undiagnosed open-angle glaucoma. Of these newly diagnosed cases, 67% of patients had previously
seen an ophthalmologist and 17% had seen an ophthalmologist in the preceding 2 years (205). In
Australia, 51% (36 of 70) of patients with undiagnosed glaucoma in the Melbourne Visual Impairment
Project had seen an ophthalmologist, optometrist, or both in the preceding year (206). Some missed
cases of COAG may have resulted from differing diagnostic criteria or from progression of disease
between assessments. More probably, missed cases arose from less accurate assessment for glaucoma.
In Sweden, among persons with newly identified openangle glaucoma after screening, 21% of those
with an IOP less than 21 mm Hg had seen an ophthalmologist in the preceding 2 years, compared with
12% of those with a screening IOP of 21 mm Hg or greater (P < 0.001) (205). Similar findings have
been reported from the Tierp Glaucoma Survey, also in Sweden. These reports suggest that the finding
of a normal IOP decreases detection of COAG in routine eye care.
The nature of opportunities to improve diagnosis for glaucoma varies widely from setting to setting. In
the United Kingdom, one study assessed practice patterns for glaucoma assessment and found that four
of five optometrists could improve their detection of glaucoma by at least 50% by performing
ophthalmoscopy and tonometry in all patients and perimetry in persons belonging to high-risk groups
(207).
Nonadherence and Undertreatment
Suboptimal treatment may also significantly hamper efforts at preventing blindness due to glaucoma.
Nonadherence to treatment and follow-up are a particular concern. In patients older than 65 years in the
New Jersey Medicaid Program who were initiated on topical agent for the treatment of glaucoma, 23%
never filled their prescription and the remainder missed an average of 30% of treatment days (208). In a
managed care setting in Massachusetts, 25% of patients newly initiated on glaucoma therapy missed at
least 20% of patient days of treatment (209). Adherence to treatment is notoriously difficult to predict
but has been found to be several times more frequent in those seen only once in the 12 months after
initiation of new treatment (209, 210). Models of care that focus on patient education in a supportive
environment have the potential to enhance patient adherence (211).
Suboptimal treatment may also result from a failure to incorporate advances in management of
glaucoma into practice. Currently, the data on quality of care for COAG are sparse. One study of U.S.
working-age patients with COAG enrolled in managed care plans found that care was consistent with
guidelines (212). However, one significant deficiency was that only 53% of patients with COAG
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received an optic nerve drawing or photograph on initial examination (212). Given the expected delays
in adopting new innovations, IOP may be undertreated in the United States and elsewhere in light of
recent clinical trials.
CHALLENGES FROM GLAUCOMA IN THE DEVELOPING WORLD
In much of the developing world, the situation with glaucoma is entirely different. Eye-care services are
limited, often severely so, and the amount of glaucoma in the general population that has been diagnosed
is small; reports of 7% of COAG in India and 2% in Tanzania are typical (41). Glaucoma usually
presents symptomatically with severe vision loss in one or both eyes, or a painful acute attack. Surgical
trabeculectomy with or without antimetabolites is the treatment of choice except in cases of angleclosure glaucoma amenable to peripheral iridotomy or iridectomy. Ongoing follow-up is typically a
hardship for patients and is often not possible. For most people with glaucoma in the developing world,
the disease simply follows its natural course without detection or intervention, at least until symptoms
develop and blindness encroaches.
Challenges to PreventinG Blindness: A Population Perspective
As the leading cause of irreversible blindness worldwide, affecting more than 6.6 million people,
blindness due to glaucoma is a mounting problem of global public health importance. Glaucoma-related
blindness is also largely preventable through timely diagnosis, effective treatment, and ongoing
monitoring. Although this seems attainable in the developed world, glaucoma has proven itself a
difficult adversary. The nature of most glaucomas is such that it typically evades detection until its final
stages unless ocular assessment is done periodically to detect the disease early in its course; glaucoma is
also unrelenting and takes advantage of any delays, lapses, or insufficiencies in treatment to destroy
remaining axons. Consequently, a health services response sufficient to prevent blindness from
glaucoma is resource intensive. Successful management of glaucoma typically requires long-term active
involvement of the patient, except in the prevention of angle-closure glaucoma with iridotomy. From a
clinical standpoint, determined efforts to detect glaucoma early and treat it effectively regularly meet
with success in many patients, but even so, glaucoma has yet to be dislodged as a major cause of
blindness in any country. Major deficiencies in the detection and treatment of glaucoma remain, even in
developed countries.
STRATEGIES FOR PREVENTING BLINDNESS: IMPROVED EARLY DETECTION
There are numerous avenues to improve the prevention of blindness from glaucoma, but improved early
detection offers the most potential. Undiagnosed glaucoma is probably the largest reservoir of
preventable blindness in the developed
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world and is second only to cataract overall in the developing world. The strategies for the identification
of asymptomatic individuals at increased risk for glaucoma run the gamut from population screening to
case finding. Population screening is the presumptive identification of individuals who might benefit
from further diagnostic assessment of glaucoma by an ophthalmologist or optometrist; case finding
involves testing for glaucoma as opportunities arise in the course of clinical care, such as during periodic
eye evaluations. A blend of approaches for detecting glaucoma from this spectrum can complement one
another and may offer the best hope of minimizing undiagnosed glaucoma.
Improving Coverage of Case Finding
In most developed countries, periodic comprehensive ocular assessments form the backbone of primary
eye care and provide as one of their chief benefits an excellent vehicle for glaucoma case finding. In
fact, rates of coverage are surprisingly good in some settings. In Australia, 81% of those 40 years and
older had had an examination by an ophthalmologist or optometrist within the previous 5 years (206).
An identical level of 5-year coverage was reported among persons without diabetes in a Canadian
population aged 30 years and older (213). Eye examinations in both these populations occurred least
frequently in younger men of lower socioeconomic status or without private insurance, and Australians
in rural areas we less likely to undergo eye examinations (206, 213).
Coverage may be increased further by improving the provision of services to underserviced segments of
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the population and targeting health promotion efforts to increase uptake of periodic ocular examinations
in these groups (214). Changing population-wide use of preventive eye examinations is not an easy task,
but even small percentage increases translate into a benefit to large numbers of individuals. An intensive
use of this strategy in Australia, including targeted mailings and print and broadcast media
announcements, successfully increased the use of retinal screening examinations in persons with
diabetes from 55% to 70%. However, a targeted mailing campaign in the United States with the same
objectives produced no sustained increase in retinal screening examinations (215).
Improving Accuracy of Case Finding
In clinical practice, the effectiveness of case finding for glaucoma in primary eye care may not be
optimal (205, 206). This may be due to the limited extent of examination carried out and undue reliance
on elevated IOP to trigger a complete evaluation for glaucoma (205, 207). In the U.S. context, the
American Academy of Ophthalmology (AAO) has recommended the following elements for a
comprehensive eye examination that pertain to improved detection of glaucoma (216): IOP, gonioscopy,
slitlamp examination of the anterior segment, optic disc and nerve fiber layer evaluation with
documentation of optic nerve appearance, and visual field examination. Alternatively, others suggest
selective performance of visual field tests depending on risk factors and clinical findings (217).
Similarly, routine gonioscopy may not be necessary in those who, on examination, have normal
peripheral anterior chamber depth and normal IOP. Careful documentation of the optic nerve appearance
at baseline examination, preferably with stereoscopic photos or other suitable imaging (such as optical
coherence tomography or scanning laser ophthalmoscopy), is important to permit glaucomatous changes
to be identified on follow-up. A good baseline evaluation for glaucoma is of particular importance in
following higher-risk patients, such as glaucoma suspects and patients with ocular hypertension, but it is
worth remembering that almost any patient can develop glaucoma. In one large population-based cohort
study, 28% of persons with newly diagnosed glaucoma were not considered to be glaucoma suspects or
to have ocular hypertension when examined 4 years earlier (58).
To maximize cost-effective glaucoma case finding, the frequency of periodic assessment should be
adjusted to a patient's level of risk for glaucoma. One recommendation for the frequency of
comprehensive eye examinations that reflects the risk for glaucoma comes from the AAO (Table 9.6):
every 1 to 2 years for those 65 years and older, every 1 to 3 years for those 55 to 64 years of age, every 2
to 4 years for those between the ages of 40 and 54 years, and 5 to 10 years for those before 40 years of
age. For persons with a first-degree relative with glaucoma or those who are of African descent (or who
have other risk factors supported by good evidence [ Table 9.7]), the frequency may be increased and
should be at least every 6 months to a year for patients 65 or older, every 1 to 2 years for those aged 55
to 64, every 1 to 3 years for those aged 40 to 54, and every 2 to 4 years for those younger than 40 years
(216). Patient referral by primary care physicians to an eye specialist for periodic comprehensive eye
examination is supported by the U.S. Preventive Services Task Force for those at increased risk for
glaucoma (223).
Table 9.6Recommended Frequency of Comprehensive Medical Eye Examinations, according to
Risk-Factor Status for Chronic Open-Angle Glaucoma
Age-Group
Frequency of Examinations
Adults with No Risk Factors
Adults with >1 COAG Risk Factor
<40y
5-10 y
Every 2-4 y
40-54 y
Every 2-4 y
Every 1-3 y
55-64 y
Every 1-3 y
Every 1-2 y
>65y
Every 1-2 y
Every 6-12 mo
aindividuals are considered to have a risk factor for COAG if they have elevated intraocular pressure or
a family history of glaucoma, or are of African or Latino/Hispanic descent. COAG, chronic open-angle
glaucoma.
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Data from American Academy of Ophthalmology (AAO) Preferred Practice Patterns Committee.
Preferred Practice Pattern Guidelines. Comprehensive Adult Medical Eye Evaluation. San Francisco,
CA: AAO; 2005. Available at: http://www.aao.org/ppp.
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Table 9.7 Variables with Good Evidence of Being Clinical Risk Factors for Chronic Open-Angle
Glaucomaa
Variable
RRfor COAG
Best Evidence: References
Age (per decade >40 y)
2
3, 42, 50, 53
Black (white, referent)
4
29
Family history (first-degree relative)
2-4
78,80,82,218
b
58, 72, 82, 102
IOP (<15 mm Hg, referent)
19-21 mm Hg
3
22-29 mm Hg
13
=30 mm Hg
40
Myopia
1.5-3
116-118,219
Exfoliation
5-10
82,102,118
Diastolic perfusion pressure (<55 mm Hg)
3
72,126,130,218
Central corneal thickness
1.4
129
c
Pigment dispersion syndrome
220
_
aTable shows only those variables meeting the standard of “good”-level evidence, as graded according
to method of the U Preventive Services Task Force (221). Display of risk-factor information modeled
after Ref. 222.
b Relative
risk data are from Ref. 53. For best evidence, see also Table 9.4 .
c The estimated
proportion of patients with pigment dispersion syndrome is 6% to 43%.
COAG, chronic open-angle glaucoma; IOP, intraocular pressure; RR, relative risk
The estimated proportion of patients with pigment dispersion syndrome is 6% to 43%.
Screening for Chronic Open-Angle Glaucoma
Screening for undiagnosed glaucoma in high-risk populations (e.g., blacks, older adults,
socioeconomically disadvantaged persons) may complement periodic ocular examination, particularly
when targeting individuals who cannot or have not accessed care (224). In some respects, COAG is an
ideal disease for population screening: It is of public health importance; detectable during its prolonged
asymptomatic phase; and amenable to effective therapy to prevent blindness, particularly when
diagnosed early. However, many obstacles to large-scale screening for COAG remain, including the lack
of an entirely satisfactory screening test and the weakness of the economic argument to justify the
resources required compared with other preventive interventions. Currently, population screening for
COAG is, for the most part, carried out sporadically and on a modest scale by community and research
groups (205).
The specifications for a suitable test for population screening for glaucoma are more exacting than the
criteria for clinical use. One set of criteria for screening devices for COAG from Prevent Blindness
America illustrates the difficult balance of specifications required: high accuracy (sensitivity, 85% for
moderate to advanced glaucoma; specificity, 95%); ease of administration and transport, set up by
minimally trained personnel; low cost and low maintenance; short testing and process time; and ease of
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understanding and conduct for the patient. These criteria emphasize high specificity to reduce the large
costs associated with false-positive referrals. For example, consider tonometry, the traditional screening
modality for glaucoma. In the Baltimore Eye Survey, a screening IOP of more than 21 mm Hg detected
only 47% of persons with COAG (i.e., sensitivity); using a criterion of IOP less than 21 mm Hg
correctly identified 92% of persons without COAG (i.e., specificity) (29). For a prevalence of about 2%,
such as in whites older than 39 years (Table 9.1), 9 of 100 persons would have a screening IOP greater
than 21 mm Hg, of whom one would have COAG and eight would have false-positive results. If a
different test were used with the same sensitivity but a higher specificity of 98%, then the number
referred for definitive testing would be reduced to only 3 in 100, consisting of one person with COAG
and two with false-positive results. This example illustrates the importance of high specificity in
glaucoma screening. The fact that an IOP greater than 21 mm Hg detects only 50% of COAG also
underlines the need for good sensitivity to avoid falsely reassuring those tested.
For varying reasons, none of the many useful diagnostic tests for glaucoma are completely satisfactory
for population screening. Tonometry is now discouraged as a standalone method for screening because
there is no IOP level that gives a reasonable balance between sensitivity and specificity (29). COAG
screening by evaluation of the optic nerve head is limited by the cost of a highly trained clinician or of a
suitable imaging device. The practicality of full threshold or thresholdrelated suprathreshold automated
perimetry is limited by learning effects, the need for skilled interpretation, and relatively high costs.
Frequency doubling perimetry may be one of the most promising psychophysical tests for population
screening for glaucoma, although the cost remains significant and the specificity may be suboptimal
unless adequate criteria are used to define an abnormal test (225).
Cost-Effectiveness of Screening for COAG
Population screening for COAG, although highly desirable, does not appear to be cost competitive with
other preventive health care interventions (226, 227). The cost per year of vision saved by glaucoma
screening appears to be many times the cost per year of life saved from such interventions as screening
for breast cancer (226). In contrast, a 1983 analysis suggested that population screening for glaucoma
would probably be cost-effective if subgroups at known higher risk for glaucoma were targeted (228).
Glaucoma screening programs have typically also screened for visual impairment, leading causes of
which include refractive error and cataracts, which are amenable to treatment. This major benefit of
glaucoma screening has not been built in to cost-effectiveness analyses. In fact, it is probably more
accurate to think of glaucoma screening as a component of a vision screening examination. Further
screening innovations and updated economic
P.162
analyses will permit a stronger case to be made in the future for cost-effective screening for COAG, at
least in high-risk segments of the population.
Screening for Angle-Closure Glaucoma
In Asian populations where angle-closure glaucoma is the predominant cause of morbidity from
glaucoma, there is great potential for screening programs to prevent angle-closure glaucoma. In contrast
to COAG, angle-closure glaucoma can be prevented by the bilateral laser iridotomies in individuals with
occludable angles, a simple one-time intervention (229). Consequently, the cost of preventing angleclosure glaucoma is much less than that of providing long-term treatment for COAG. The risk for
blindness is also much higher for angleclosure glaucoma than for COAG and therefore the benefit is
greater for each case of angle-closure glaucoma prevented (31, 39, 40). As a result, population screening
for angle-closure glaucoma in appropriate populations may be much more costeffective than population
screening for COAG.
Numerous modalities have been suggested for population screening for occludable angles, including
anterior chamber depth measurement, Van Herick test (or peripheral anterior chamber depth
measurement), and the oblique flashlight test. However, the accuracy of the tests is not completely
satisfactory for population screening and varies with the biometric characteristics of the population (40).
For an acceptable sensitivity of about 85%, both anterior chamber depth measurement (<2.22 mm by
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optical pachymetry) and Van Herick test (peripheral anterior chamber depth <15% peripheral corneal
thickness) could achieve specificities of only 84% and 86%, respectively, for detecting occludable
angles in a Mongolian population (40, 230).
A clinical trial is under way in Mongolia to determine whether population screening and prophylactic
iridotomies for occludable angles will reduce the incidence of angle-closure glaucoma (231). The
screening criteria of an anterior chamber depth of less than 2.53 mm (by ultrasonography) or an IOP
greater than 24 mm Hg tagged almost one third of the screening population for a definitive evaluation
including gonioscopy; 24% had occludable angles. Although appropriate for the purposes of a clinical
trial, more specific tests or criteria would greatly improve the feasibility of large-scale screening for
angle-closure glaucoma.
Strategies for Prevention in the Developing World
In much of the developing world, the tremendous scarcity of resources for eye care greatly limits the
feasible interventions to prevent blindness from glaucoma. It has been suggested that the best workable
option in much of the developing world may be to integrate glaucoma case finding into other blindness
prevention efforts, such as cataract surgical programs, and to offer inexpensive and high-quality filtering
surgery for those cases of surgical glaucoma identified (232) and peripheral iridotomy for those with
occludable angles.
Teleglaucoma: Using Distance Technology to Improve Access to Care
Given progress in information technology, it is possible to obtain high-quality digital photographs of the
optic nerve and transmit compressed images for storage, retrieval, and evaluation via Web-based
platforms. Such an approach, with or without recommendations on management of patients, is referred
to as teleglaucoma.
Given that camera systems are portable, and assuming that a high-speed Internet link exists, it should be
possible to set up mobile units or multiple fixed centers, which facilitate access to eye examinations so
that patients do not need to travel a great deal unnecessarily (233). These images can be stored and read
from a distance, and patients can be triaged into healthy, suspect, or definite categories. Referral and
treatment decisions can be made as appropriate and conveyed to the patient via trained ophthalmic
personnel (e.g., nurse or technician). Compression can take place without altering the quality of images
significantly, and digital images appear to provide comparable information for the purposes of grading
glaucomatous optic nerve involvement as traditional stereo slide film (234, 235). More work is needed
to assess whether two-dimensional images of the nerve convey adequate information, compared with
stereoscopic images.
The deployment of advanced technologies can minimize the barriers of distance and geography to
enhance access and facilitate the delivery of integrated health care (236). This is particularly important
in areas with large underserved or rural populations or a limited number of ophthalmologists (237).
SUMMARY
Glaucoma is the leading cause of irreversible blindness worldwide, and by 2020, the number of
persons with glaucoma will almost double from the recent estimate of 67 million.
The prevalence of COAG and angle-closure glaucoma varies across different populations: COAG
accounts for about 90% of all glaucoma in blacks, whites, and some Asian populations (e.g.,
Japanese); angle-closure glaucoma predominates in certain Asian populations (e.g., Inuit,
Mongolian) and has a similar prevalence to COAG in others (e.g., Chinese in Singapore).
The age-specific prevalence of COAG (by population) is a useful starting point for clinicians to
estimate the probability of COAG when beginning an initial assessment.
Clinical risk factors are useful to assess the risk of COAG, but only a small number are well
supported by evidence: age, race (black), elevated IOP, family history (first-degree relative),
myopia, exfoliation syndrome, and diastolic ocular perfusion pressure (<55 mm Hg).
The onset and progression of most glaucomas occur so slowly that careful documentation of
baseline examination, including the optic nerve head appearance, is required to detect subtle
changes.
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The lifetime risk for blindness from COAG probably exceeds 5% on average; risk factors for
blindness from COAG include
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early age of onset, advanced stage, inadequate IOP control, and a high rate of progression despite
treatment.
Undiagnosed COAG is probably the largest reservoirvoir preventable blindness in the world in
that only 50% of COAG cases are identified, even in developed countries. A pressing need exists
to complement this by developing cost-effective approaches for screening high-risk groups for
COAG.
In some Asian populations, screening and treatment of occludable angles with laser iridotomy to
prevent angle-closure glaucoma may soon be demonstrated to be effective and feasible.
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10 - The Glaucoma Suspect: When to Treat?
> Table of Contents > SECTION II - The Clinical Forms of Glaucoma > 10 - The Glaucoma Suspect:
When to Treat?
10
The Glaucoma Suspect: When to Treat?
Distinguishing healthy persons in the general population from those at considerably increased risk for
chronic open-angle glaucoma (COAG) is important because patients in the latter group—commonly
referred to as ‘glaucoma suspects’—need to be followed up more carefully to decide whether and how to
begin prophylactic therapy. This chapter outlines the definition and prevalence of glaucoma suspect and
reviews key diagnostic elements that need to be considered. The chapter also highlights challenges in
management, summarizing the results of the Ocular Hypertension Treatment Study (OHTS), and
addresses when it may be appropriate to initiate therapy. Practical guidelines for follow-up are also
offered.
TERMINOLOGY
The term ocular hypertension was advocated in the 1970s to distinguish persons with ‘normal’
intraocular pressure (IOP) (i.e., =21 mm Hg) from those with an IOP greater than 21 mm Hg, who were
considered to be at increased risk for COAG (1, 2). Chandler and Grant (3) suggested referring to this
condition as early open-angle glaucoma without damage.
However, in addition to those with consistently elevated IOP, there are individuals who exhibit optic
nerve features suggestive of early glaucoma or who have suspicious visual field defects. To include
these categories and identify a subpopulation of individuals or eyes at increased risk for COAG
glaucoma (Table 10.1) (4), the term ‘glaucoma suspect’ was advocated by Shaffer (5). There are also
patients at higher risk for angle-closure glaucoma—for example, those with an occludable angle as
determined by gonioscopy. Given recent advances in molecular genetics, there are also patients who can
be identified as having an elevated risk for glaucomatous optic nerve damage by virtue of harboring one
or more diseasecausing genetic mutations (see Chapter 8). In this chapter, we will use the term glaucoma
suspect in the context of a patient at greater-than-average risk (compared with the general population)
for COAG. (Individuals at increased risk for angleclosure glaucoma are discussed in Chapter 12, and
those at increased risk by virtue of a genetic susceptibility are discussed in Chapter 8.)
Table 10.1 Definition of a Glaucoma Suspect
Open angle by gonioscopy and one of the following in at least one eye:
IOP consistently >21 mm Hg by applanation tonometry
Appearance of the optic disc or retinal nerve fiber layer suggestive of glaucomatous damage
Diffuse or focal narrowing or sloping of the disc rim
Diffuse or localized abnormalities of the nerve fiber layer, especially at superior and inferior poles
Disc hemorrhage
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Asymmetric appearance of the disc or rim between fellow eyes (e.g., cup-to-disc ratio difference >
0.2), suggesting loss of neural tissue
Visual fields suspicious for early glaucomatous damage
Adapted from American Academy of Ophthalmology. Primary Open-Angle Glaucoma Suspect,
Preferred Practice Pattern. San Francisco, CA: American Academy of Ophthalmology, 2005. Available
at: http://www.aao.org/ppp.
PREVALENCE AND DEVELOPMENT OF CHRONIC OPEN-ANGLE GLAUCOMA
Studies that have used a definition of IOP greater than or equal to 21 mm Hg in one or both eyes (with
normal visual fields and optic nerves) have reported a prevalence rate of 4% to 10% in persons older
than 40 years (6, 7, 8, 9, 10 and 11).
Patients considered to be glaucoma suspects on the basis of elevated IOP have a rate of progression to
COAG of approximately 1% per year over 5 to 15 years (Table 10.2) (12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24 and 25). In the OHTS (22), a randomized trial of topical ocular hypotensive treatment
versus close observation in participants with ‘ocular hypertension,’ the cumulative probability of
developing COAG over 5 years was about 1% per year in the medication group and about 2% per year
in the observation group. In patients who are at higher risk for developing glaucomatous optic nerve
damage (see risk factors in Table 10.3), the rate is approximately 3% to 5% per year (26, 27 and 28).
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Table 10.2Incidence of Chronic Open-Angle Glaucoma (COAG) among Persons with Ocular
Hypertension
a
Patients
with
Ocular
Observation Patients Developing COAG,
Study
Hypertension, n
Period, y
n (%)
Perkins, 1973(12) 124
5-7
4 (3.2)
Walker, 1974(13) 109
11
11 (10.1)
Wilensky et al.,
50
Mean, 6
3(6.0)
1974(14)
Norskov, 1970(15) 68
5
0
Linner, 1976(16)
92
10
0
Kitazawa et al.,
75
Mean, 9.5
7(9.3)
1977(17)
David et al., 1977 61
Mean, 3.3 Range, 1- 10(16.4)
(18)
11
Hart et al., 1979(19) 92
5
33 (35.9)
Armaly et al., 1980 5886
13
98(1.7)
(20)
Lundberg et al.,
41
20
14(34.1)
1987(21)
Kass et al., 2002
5
89(10.9)
819b
(22)
a Numbers in parentheses are reference numbers.
a Control arm.
Although elevated IOP is a major risk factor for COAG, normotensive individuals can develop
glaucoma. Some of these patients may have normal-tension glaucoma (see Chapter 11), whereas others
may demonstrate elevated IOP at subsequent examinations (12, 23).
SCREENING AND EARLY DETECTION
Screening is discussed in Chapter 9. In brief, if an IOP value of more than 21 mm Hg is used for
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screening, then there is a high rate of false-positive and false-negative results for COAG. Skilled optic
nerve examination is good but not always practical. Standard automated perimetry (SAP) can detect
glaucomatous defects, but by the time a defect is detected, a substantial loss of axons has often occurred
(29, 30). A number of studies have demonstrated that defects on short-wavelength automated perimetry
(SWAP) and frequency doubling technology (FDT) perimetry can precede development of SAPdetected defects in patients with elevated IOP. Table 10.4 provides a comparative summary of these
types of perimeters (31). Imaging devices may also be useful in the early detection of glaucoma. (These
are covered in greater detail in Chapter 4 and below.)
Table 10.3 High-Risk Glaucoma Suspects
High-risk glaucoma suspects include patients who have one or more of the following:
a
IOP consistently >30 mm Hg
Thin central corneal thickness (dependent on ethnicity)3
Vertical cup-to-disc ratio >0.7a
Older agea
Abnormal visual field, e.g., increased pattern standard deviation on Humphrey Visual Field testa
Presence of exfoliation or pigment dispersion syndrome
Disc hemorrhagea
Family history of glaucoma or known genetic predisposition
Fellow eye of patient with severe unilateral glaucoma (excluding secondary unilateral glaucoma)
Additional ocular (e.g., suspicious disc appearance, myopia, low optic nerve perfusion pressure,
steroid responder) or systemic risk factors that might increase the likelihood of developing
glaucomatous nerve damage (e.g., African ancestry, sleep apnea, diabetes mellitus, hypertension,
cardiovascular disease, hypothyroidism, myopia, migraine headache, vasospasm)
a These factors were identified as significant risk factors for development of chronic open-angle
glaucoma in the Ocular Hypertension Treatment Study and the European Glaucoma Prevention Study.
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Table 10.4 Comparison of Advantages and Limitations of Manual Perimetry, SAP, SWAP, and
FDT Perimetry
Method
Merits
Limitationsa
Manual
Long track record
Not standardized among
(Goldmann)
different laboratories
perimetry
Useful in patients who cannot perform automated
perimetry (e.g., those with poor reliability, small field Not readily available in office
of vision, or unreliable SAP results, or who are much
older adults)
Absence of statistical software
analysis
SAP
Fully validated by long clinical experience and major Relatively difficult to perform,
clinical trials
learning effect, artifacts
possible, poor patient
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Screening and fast threshold techniques (e.g., SITA)
available
SWAP
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acceptance
Long track record, stable technology
Difficult to apply in screening
situations
Easy to read and intuitive printouts
Not portable
Diagnostic and progression statistical tools available
Relatively expensive
High penetration in ophthalmology and optometry
practices
Might detect changes earlier than SAP (still
controversial)
More difficult to perform than
SAP
Fast threshold technique available
More affected by cataracts
Tested in long-term studies
FDT perimetry Might detect changes earlier than SAP (still
controversial)
Relatively portable
No progression software
Limited evaluation in long-term
studies
Screening and fast threshold techniques available
Evolving technique, relatively
short track record for Matrix
device
Tested in screening situations
No progression software
Good test-retest variability profile
Favorable patient acceptance
limitations to all techniques include a lack of consensus on what constitutes a defect or
progression; relatively crude reliability indices; poor acceptance by patients; and relatively long duration
for threshold tests, even with fast techniques.
FDT, frequency doubling technology; SAP, standard automated perimetry; SITA, Swedish interactive
thresholding algorithm; SWAP, short-wavelength automated perimetry.
Modified from Canadian Ophthalmological Society evidence-based clinical practice guidelines for the
management of glaucoma in the adult eye. Can J Ophthalmol. 2009;44(suppl 1):S7-S93.
According to the American Academy of Ophthalmology, the best method to detect early glaucoma is a
comprehensive eye evaluation, which includes assessment of the IOP, optic nerve, and visual field (see
Chapter 9). Guidelines for frequency of screening for glaucoma are listed in Table 10.5 (4).
Intraocular Pressure and Pachymetry
To detect any change in IOP, optic nerve, or visual field status (i.e., early progression with structural or
functional damage evident), it is essential to obtain good baseline documentation. In the case of IOP, it
is worthwhile to measure central corneal thickness (CCT) with a pachymeter (Fig. 10.1). Patients
classified as glaucoma suspects have been reported to have a higher CCT than individuals with COAG
or healthy individuals (32, 33 and 34), with 42% of glaucoma suspects having a CCT of greater than 585
µm (34). This is significant because the Goldmann applanation tonometer was calibrated for a CCT of
approximately 530 |µm (35, 36). Any significant deviation from this induces an artifact of measurement.
It has been estimated that 30% to 57% of elevated IOPs in glaucoma suspects are actually artifacts of
measurement (33, 37, 38).
There is no universally accepted formula, however, that can be applied to ‘correct’ the IOP measurement
a Some
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for any given CCT. Based on a review of various correction-factor approaches, the range probably falls
between 2.5 and 3.5 mm Hg per 50 |µ of difference from normal (39). Hence, if a patient's CCT
measured 650 |µ (in the absence of any visible corneal pathology), then the ‘true’ IOP would likely be
several millimeters of mercury less than measured. To avoid confusion, however, when sharing patient
information with other practitioners, it is recommended that IOP should always be communicated as the
measured IOP rather than a ‘corrected’ IOP.
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Table 10.5 Recommended Guidelines for Follow-up of a Glaucoma Suspect, American Academy of
Ophthalmology
Treatment
Target IOP Achieved
High Risk
Follow-up Interval, mo
Examination
ONH/VF Evaluation
No
N/A
No
6-24
6-24
No
N/A
Yes
3-21
6-18
Yes
Yes
Yes
3-12
6-18
Yes
No
Yes
=4
3-12
IOP, intraocular pressure; N/A, not applicable; ONH, optic nerve head; VF, visual field.
Modified from American Academy of Ophthalmology. Primary Open-Angle Glaucoma Suspect,
Preferred Practice Pattern.
San Francisco, CA: American Academy of Ophthalmology, 2005. Available at: http://www.aao.org/ppp.
Slitlamp Biomicroscopy and Gonioscopy
Baseline documentation requires precise slitlamp examination and gonioscopy to exclude secondary
causes of glaucoma. This includes angle closure and other secondary causes, such as angle recession,
pigment dispersion, and inflammatory forms of glaucoma. After dilation, the anterior lens capsule
should be examined for the presence of exfoliation.
Fundus Examination
In the posterior segment, it is important to document the appearance of the optic nerve head with careful
drawings or stereo optic nerve head photos. Optic nerve head imaging devices (e.g., confocal laser
scanning tomography) may also be useful. It is also worth studying the disc rim carefully for small
hemorrhages, because these can precede visual field loss and future optic nerve damage. Similarly, the
appearance of the nerve fiber layer (NFL) can be noted using red-free (green) light. It is important to
document the presence or absence of NFL defects. Additional tools to document the NFL include laser
polarimetry with the nerve fiber analyzer, scanning laser ophthalmoscopy, and optical coherence
tomography (OCT) (see Chapter 4).
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Figure 10.1Proper technique for measuring CCT, with probe placed perpendicular to central cornea. A
structurally thick cornea can artifactually raise measured applanation IOP
Visual Fields
An attempt should be made to obtain two or three baseline visual fields. Our preferred options include
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one or more of the following: (a) 24-2 Swedish interactive threshold algorithm (SITA) standard on
Humphrey field analyzer II perimeter, (b) 24-2 full threshold white-on-white Humphrey perimetry or
equivalent program on a different automated perimeter, (c) FDT (matrix preferred) or SWAP.
If an abnormality is found, it needs to be confirmed on repeated visual field examination. This was
dramatically illustrated in OHTS (40). Over a 5-year period, 21,603 visual fields were obtained from
1637 OHTS participants. When follow-up visual field results were outside the normal limits on the
Glaucoma Hemifield Test, the Corrected Pattern Standard Deviation, or both, follow-up visual fields
were obtained to confirm the abnormality. Results of 748 visual fields were abnormal; of these, 703
(94%) were abnormal and reliable, and 45 (6%) were abnormal and unreliable. On retesting,
abnormalities were not confirmed for 604 (85.9%) of the originally abnormal and reliable visual fields.
Hence, most visual field abnormalities in OHTS participants were not verified on repeated testing and
were probably due to the learning curve or long-term variability in the visual field.
Imaging of the Optic Nerve and Nerve Fiber Layer
Photographic assessment of the optic nerve head remains a mainstay in the diagnosis and management
of glaucoma suspects. However, there are imaging tools capable of
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documenting the topographic features of the optic nerve head and measuring the thickness of the retinal
NFL that can be useful adjuncts in the management of glaucoma suspects. These tools are reviewed in
Chapter 4 and include the confocal scanning laser ophthalmoscope (manufactured as Heidelberg retinal
tomography [HRT]), OCT, and scanning laser polarimetry (e.g., the GDx nerve fiber analyzer with
variable corneal compensator [GDx-VCC]). Each of the technologies has good reproducibility and
provides objective and quantitative analysis of ocular structure. An evidence-based medicine review of
these technologies by the American Academy of Ophthalmology (41) came to the following conclusion:
The [optic nerve head] and [retinal] NFL imaging devices provide quantitative information for the
clinician. Based on studies that have compared the various available technologies directly, there is no
single imaging device that outperforms the others in distinguishing patients with glaucoma from controls
The information obtained from imaging devices is useful in clinical practice when analyzed in
conjunction with other relevant parameters that define glaucoma diagnosis and progression.
Ocular Blood Flow
Whether blood flow to the optic nerve is reduced in glaucoma suspects and may be an early finding in
the course of COAG remains to be proven. However, in one study using laser Doppler flowmetry, optic
nerve head blood velocity, volume, and flow in four quadrants of the nerve were compared in patients
with COAG, glaucoma suspects, and healthy participants (42). In the eyes of glaucoma suspects, flow
was significantly lower in the superotemporal rim (16% lower), the cup (35% lower), and the
inferotemporal neuroretinal rim (22% lower), compared with that in the controls. No significant
difference between glaucoma suspect and control eyes was seen in the inferonasal rim or superonasal
rim, and no significant difference was detected at any location between glaucoma suspect eyes and eyes
with COAG. Further data are needed to clarify whether a reduction in blood flow to the optic nerve head
plays a significant role in early damage to some optic nerves.
RISK FACTORS
The risk for glaucoma increases with the number and strength of risk factors. Studies that have evaluated
risk factors in this context include longitudinal population studies and randomized, controlled trials
comparing treatment with no treatment in persons with ocular hypertension (43).
Longitudinal population studies, such as the Barbados Incidence Study of Eye Diseases (BISED), the
Melbourne Visual Impairment Project (Melbourne VIP) and the Rotterdam Eye Study (RES), provide
information on risk factors that are involved in progression from normal to COAG. The most relevant
risk factors consistently found in all three studies are older age at baseline and an approximately 1-mm
Hg increase in IOP at baseline. BISED and RES reported a 4% and 6% risk, respectively, of developing
glaucoma for persons 1 year older versus baseline (baseline mean, 56.9 years in BISED and 65.7 years
in RES). In all three studies, there was a 10% to 14% increased risk among persons with a baseline IOP
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1 mm Hg or more higher than the average for the population of developing COAG over the following 5
to 9 years. Other risk factors in these studies include a family history of COAG, a thinner CCT, and
lower ocular perfusion pressures (systemic blood pressure minus IOP) in BISED; the use of systemic
calcium-channel blockers for the treatment of systemic hypertension in the RES; and exfoliation, large
cup-to-disc ratios of the optic discs, or use of systemic a- agonist blockers in VIP.
High-quality studies examining the risk for progression from normal to glaucoma in those with ocular
hypertension include the OHTS and the European Glaucoma Prevention Study (EGPS) (22, 44). In
OHTS, 1636 patients, aged 40 to 80 years, with no evidence of glaucomatous damage and with IOP
between 24 and 32 mm Hg in one eye and between 21 and 32 mm Hg in the other eye were randomly
assigned to either observation or treatment with topical medication. The goal in the medication group
was to reduce the IOP by 20% or more and to reach an IOP of 24 mm Hg or less. In EGPS, 1081
patients aged 30 years or older with an IOP between 22 and 29 mm Hg were enrolled. Patients were
randomly assigned to treatment with dorzolamide or placebo. Open-angle glaucoma in both studies was
defined as the development of reproducible visual field abnormality or reproducible finding of optic
nerve deterioration. Factors consistently identified in both studies as predictive of COAG development
included elevated IOP, large cup-to-disc ratio, older age, thinner CCT, and higher pattern standard
deviation values on the Humphrey automated perimeter. The EGPS also found vertical cup-to-disc
asymmetry to be an important predictive factor (45). Other longitudinal studies have also shown
suspicious disc appearance, myopia, and family history of glaucoma to be risk factors for the
development of glaucomatous optic neuropathy and visual field loss (46, 47 and 48). In OHTS and
EGPS, predictive factors that occurred after baseline were a higher mean IOP during followup, a smaller
IOP reduction from baseline, and optic disc hemorrhages (43). In addition, in EGPS the use of systemic
diuretics to treat systemic hypertension during follow-up increased the risk for COAG. Interestingly,
long-term fluctuation in IOP and diurnal fluctuation in IOP have not been associated with the
development of COAG (44, 46).
Risk Calculators
The risk for COAG in patients who are considered glaucoma suspects on the basis of elevated IOP can
be estimated with risk calculators (49). The most recent risk calculators are available online and
incorporate data from OHTS; EGPS; and another longitudinal study, the Diagnostic Innovations in
Glaucoma Study (DIGS). This pooled analysis, which provides the 5-year risk for COAG in one eye in a
patient aged 40 years with ocular hypertension, has narrowed the 95% confidence limits for prediction
and strengthened the generalizability of the results.
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Given the studies that risk calculators are based on, calculations may not apply to patients who are
younger than 40 years, nonwhite or of African descent, and do not have an IOP of 22 mm Hg or higher.
Risk calculators also do not provide critical information that may guide therapy, such as life expectancy
and psychological and social factors. The calculators may provide supplementary information for the
physician and the patient, but caution needs to be exercised, as the clinical decision to treat is complex
and involves taking the best available evidence and tailoring it to the individual patient.
WHEN TO TREAT
Whether to begin treatment in a glaucoma suspect is a complex decision that involves consideration of
many factors, including visual, physical, medical, psychological, and social circumstances (50). Every
attempt should be made to engage the patient in the decision-making process, because potentially
exposing the patient to long-term therapy when there is no definite evidence of glaucomatous optic
nerve damage is a major decision.
If the IOP is elevated, we suggest first stratifying the patient into low, moderate, or high risk for
progression (Table 10.3 and Table 10.6). The OHTS and EGPS results should be kept in mind for
identifying high-risk groups. In the OHTS, for those with a mean baseline IOP greater than 25.75 mm
Hg, the risk for glaucomatous optic nerve damage at 5 years was 36% if the patient had a thin or average
(555 |µm) cornea, and 13% with a CCT of 565 to 588 |µm. For a cup-to-disc ratio of more than 0.3, the
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risk for those with a thin or average cornea was 24%, and for those with a thickness of 565 to 588 µm
was 16%.
Patients at high risk for progression warrant treatment to prevent optic nerve damage, whereas those at
low risk can be observed at periodic intervals (51). If there is a moderate risk for progression, then a
decision can be made to treat or observe at more frequent intervals than patients at low risk. If the IOP is
not elevated and the disc or visual field is suspicious, there is no compelling evidence to guide clinicians
regarding whether to treat or to simply observe.
Table 10.6Making the Decision to Treat in Glaucoma Suspects with Elevated IOP
Stratify patients into low, moderate, or high risk for progression (based on best available evidence and
clinical judgement):
High risk: Suggest treatment be initiated
Moderate risk: Can initiate treatment if appropriate, or monitor closely
Low risk: Monitor IOP as well as optic nerve structure and function, and treat if evidence of
progression
Carefully consider these factors when deciding whether to treat:
Greater age and life expectancy
Psychological factors
Convictions (patient and physician)
Social environment
Availability for follow-up
Pregnancy
The results of the OHTS indicate that reducing IOP by at least 20% (and to <24 mm Hg) in patients with
elevated IOP and no evidence of glaucomatous damage can reduce the risk for COAG by more than half
over a 5-year period (from 9.5% in the observation group to 4.4% in the medication group). However,
although topical hypotensive medication was effective in delaying or preventing the onset of COAG in
this group of patients, the results do not imply that all patients with borderline or elevated IOP should
receive medication. In fact, most cases of elevated IOP did not progress to glaucoma over the 5- year
follow-up. Furthermore, results of the EGPS suggest that patients treated with dorzolamide progressed at
the same rate as patients receiving a placebo. However, this result is controversial and may relate to
selective dropout of treated and untreated patients with higher IOPs and to the failure to achieve
sufficient lowering of IOP (52).
If there is evidence of damage to or deterioration of the optic nerve or visual field in one or both eyes,
then the patient's diagnosis changes to early COAG, and treatment should commence according to the
principles outlined in Chapters 27 and 35. Kass (53) also suggests a lower threshold for treatment in
patients with only one functional eye, where it is not possible to obtain reliable visual fields, or in
patients in whom the optic disc cannot be visualized.
In its 2005 Preferred Practice Pattern, the American Academy of Ophthalmology recommends that,
when deciding whether therapy is warranted, a risk-benefit analysis should be done, and the likelihood
of development of glaucomatous optic nerve damage should be carefully weighed against the risks of
treatment (4). The decision should be individualized, taking into account the rate at which glaucomatous
optic nerve damage and visual impairment are likely to occur, the patient's life expectancy, and the
patient's tolerance for effective treatment.
APPROACH TO TREATMENT
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If a decision is made to treat, the choice of treatment should be governed by selecting a topical
medication that will likely achieve the target IOP range (see discussion in Chapter 27)
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with the least risk to ocular or systemic health and quality of life for the patient. Cost and convenience
may also enter into this decision. Patients should be educated about the disease process and the rationale
and goals of therapy, so that they can participate meaningfully in the development of an optimal
treatment plan.
Whether laser trabeculoplasty has a role in early treatment of glaucoma suspects remains controversial.
In our opinion, laser trabeculoplasty may be indicated, and it can be a useful adjunct in decreasing IOP
by 20% to 25% if the target IOP range cannot be achieved with use of one or two medications.
Surgery is rarely, if ever, indicated as first-line therapy in a glaucoma suspect. However, trabeculectomy
or other surgical approaches may be indicated if the patient has an extremely high, uncontrolled IOP
(corrected for pachymetry) that the physician believes is certain to cause glaucomatous damage (i.e., 40
to 50 mm Hg). Additional factors such as poor adherence to medical therapy, inability to tolerate
medical therapy (e.g., benzalkonium chloride sensitivity), quality of life, and longevity of the patient
may need to be considered when deciding which IOP-lowering approach is best for the patient.
GUIDELINES FOR FOLLOW-UP
Follow-up of the glaucoma suspect is necessary to determine whether there is a change in the IOP, optic
nerve head, or visual field status over time.
The frequency of follow-up visits depends on several factors: whether the patient is receiving medical
therapy, whether the target IOP range has been achieved, and the number of risk factors for COAG the
patient has. We believe that follow-up of glaucoma suspects should occur at least every 6 to 12 months,
and more frequently in high-risk patients, especially those on treatment in whom the target IOP has not
been achieved. There are no hard and fast rules on this subject, although the American Academy of
Ophthalmology has developed some guidelines that represent the consensus of an expert panel and are
listed in Table 10.5(4).
At each visit, the IOP should be assessed, and the clinician should document whether the appearance of
the optic nerve head has changed since baseline. Visual fields should be obtained once every 6 to 18
months and compared with the baseline measurement. Gonioscopy should be repeated if there is a
suspicion of angle closure or other angle abnormality. Gonioscopy should also be considered if the
patient is given a miotic agent, because this type of treatment can induce pupillary block and formation
of peripheral anterior synechiae.
KEY POINTS
The term ‘glaucoma suspect’ is typically used when the patient has an IOP greater than 21 mm Hg
with normal discs and visual fields, or an appearance of the optic nerve head, NFL, or visual field
that is suggestive of but not definitive for glaucoma. It can also be used when the optic nerve or
visual field is suspicious for optic nerve damage.
The physician should document good baseline data, including IOP, pachymetry, optic nerve head,
NFL, and visual fields, so as to have a benchmark to assess whether progression has occurred on
follow-up visits. The CCT should be measured routinely to assess the level of risk of these
patients.
Baseline factors that consistently predict the development of COAG in major prospective studies
include older age, larger vertical or horizontal cup-to-disc ratio, higher IOP, greater pattern
standard deviation, and thinner CCT. These criteria can be used to stage the glaucoma suspect into
low, moderate, or high risk for progression.
The decision to initiate therapy in a glaucoma suspect should be based on the patient's risk for
developing visual loss; his or her systemic, psychological, and social health; and his or her
preference.
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Ophthalmol. 1977;95(4):586-587.
2. Phelps CD. Ocular hypertension: to treat or not to treat. Arch Ophthalmol 1977;95(4):588-589.
3. Chandler PA, Grant WM. ‘Ocular hypertension’ vs. open-angle glaucoma. Arch Ophthalmol. 1977;95
(4):585-586.
4. American Academy of Ophthalmology. Primary Open-Angle Glaucoma Suspect, Preferred Practice
Pattern. San Francisco, CA: American Academy of Ophthalmology, 2005. Available at:
http://www.aao.org/ppp. Accessed June 10,2010.
5. Shaffer R. ‘Glaucoma suspect’ or ‘ocular hypertension.’ Arch Ophthalmol. 1977;95(4):588.
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11 - Chronic Open-Angle Glaucoma and Normal-Tension Glaucoma
> Table of Contents > SECTION II - The Clinical Forms of Glaucoma > 11 - Chronic Open-Angle
Glaucoma and Normal-Tension Glaucoma
11
Chronic Open-Angle Glaucoma and Normal-Tension Glaucoma
TERMINOLOGY
Chronic Open-Angle Glaucoma
As discussed in Chapter 7, the glaucomas have traditionally been classified according to primary and
secondary forms. Within the former group, and indeed among all the glaucomas, by far the most
prevalent condition has been commonly referred to as primary open-angle glaucoma. Continued
research, however, has shown the concept of primary and secondary glaucomas to be arbitrary and one
that should probably be abandoned. Research has also suggested that the view of primary open-angle
glaucoma as a single entity is no longer valid. An alternative term, which we have elected to use in this
text, is chronic open-angle glaucoma (COAG). Other synonymous terms that may also appear in the
literature include chronic simple glaucoma, idiopathic open-angle glaucoma, and openangle glaucoma.
COAG is typically characterized by (a) an open, normal-appearing anterior chamber angle and increased
intraocular pressure (IOP) without any apparent ocular or systemic abnormality that might account for
the elevated IOP and (b) typical optic nerve head damage or glaucomatous visual field damage (as
described in Chapters 4 and 5, respectively). A proposed definition of COAG (modified from the
American Academy of Ophthalmology Preferred Practice Guidelines, 2005 (1)) is a multifactorial optic
neuropathy in which there is characteristic atrophy of the optic nerve. Although abnormally elevated
IOP had long been considered part of the definition, it is now considered a risk factor for COAG.
Ocular Hypertension or Glaucoma Suspect
Patients who have an IOP above 21 mm Hg for which there is no apparent cause but whose optic nerve
heads and visual fields are normal are commonly said to have ocular hypertension (2, 3). Chandler and
Grant (4) suggested the term “early openangle glaucoma without damage” for this condition, whereas
Shaffer (5) preferred the term “glaucoma suspect” (see Chapter 10). The latter term may also include
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other factors that make the possibility of glaucoma more likely, such as suspicious optic nerve heads or
visual fields. Whatever term one chooses to use for this condition, the most important point is that both
physician and patient be fully aware of its potential consequences.
Normal-Tension Glaucoma
At the other end of the spectrum with regard to susceptibility to high IOP are patients with open,
normal-appearing anterior chamber angles who have glaucomatous optic nerve head and visual field
damage despite pressures that have never been documented above 21 mm Hg. These patients are said to
have normal-tension glaucoma (NTG). The term “low-tension glaucoma” has also been used, although
the IOP in these individuals is usually “normal” or “high normal” and is rarely “low normal.” The
criteria used to define NTG over the past 25 years have been highly variable (6). Some investigators
believe that NTG is a variant of COAG, whereas others believe that the mechanism of optic atrophy in
the two conditions is different (7). Although a number of differences between the two disorders have
been described (see later text), COAG and NTG appear to represent a continuum of glaucomas in which
the mechanism of the glaucomatous optic neuropathy shifts from predominantly elevated IOP in the
former to additional IOP-independent factors in the latter, with considerable overlap of causative factors.
Chronic Open-Angle Glaucomas with Associated Abnormalities
Some forms of open-angle glaucoma, such as pigmentary glaucoma and the exfoliation syndrome, have
been identified as distinct entities because of a partial understanding of associated, causative
abnormalities and mechanisms of aqueous outflow obstruction. (These conditions are discussed in this
section of the book.) Here, the focus is on those open-angle glaucomas for which laboratory and clinical
findings have yet to clarify the glaucoma mechanisms and in which IOP plays a variable role. As the
search continues into the causes and mechanisms of the open-angle glaucomas, especially in the field of
molecular biology, an ever-increasing number of separate entities will likely be recognized within this
spectrum of disorders.
EPIDEMIOLOGY
Significance of Intraocular Pressure
The commonly used IOP level of 21 mm Hg is based on the concept that two standard deviations above
the mean within a Gaussian distribution for the white population represents the upper limit of “normal”
for that biological parameter. However, because the distribution of IOP in the general population is
skewed to the right, or to higher pressures, this principle provides only a rough approximation of the
normal limits. More important, many eyes will not develop glaucomatous optic atrophy or visual field
loss, at least not for long periods of time, despite having IOP well above 21 mm Hg, whereas others will
have progressive glaucomatous damage at pressures that are
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never observed to exceed this level. These latter observations have brought into question the role of IOP
in the mechanism of COAG. Even though many studies have confirmed a correlation between the level
of IOP and the rate of visual field loss in some groups of patients with COAG, this correlation is not
seen in all cases (8, 9 and 10). Other causative factors figure into the formula for glaucomatous damage,
which appears to explain the lack of absolute correlation between IOP and the development of COAG.
In any case, this discrepancy between IOP level and glaucomatous damage has led to the use of
additional terms within the general category of COAG, and these are reviewed hereunder.
Frequency among the Glaucomas
COAG is clearly the most common single form of glaucoma, although it is difficult to precisely
establish the proportion of individuals with this disorder to the total number of patients with all forms of
glaucoma. In a British survey of 4231 individuals between the ages of 40 and 75 years, one third of the
glaucoma population and 0.28% of the general population had COAG (11). However, in a study of 8126
individuals in Japan who were at least 40 years of age, COAG accounted for 73% of the glaucomas
detected (exclusive of patients with ocular hypertension), of which most were NTG (12). These
epidemiologic surveys will obviously be influenced by the population being studied as well as the
methods and criteria used to identify patients with glaucoma.
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Prevalence in General Populations
Several large surveys have been conducted to determine the number of patients with ocular hypertension
and COAG (or glaucoma in general) within a population at a given time (reviewed in Chapters 9 and
10). The prevalence of glaucoma in persons older than 40 years is between 1% and 2% in most studies,
although reports again vary considerably according to the population studied and the diagnostic criteria
and screening techniques used (13, 14).
Natural History of Visual Field Loss in Chronic Open-Angle Glaucoma
Leydhecker (15) studied the distribution of IOP and glaucomatous visual field loss in a large population
survey. When persons with pressures higher than 20 mm Hg and those with definite glaucomatous field
defects were plotted against their age, the two slopes were parallel and separated horizontally by 18
years, which led to the notion that 10 to 20 years may elapse between the onset of ocular hypertension
and the development of visual field loss. Lichter and Shaffer (16), however, found that field loss in a
population of 378 patients with ocular hypertension, observed for an average of 12.75 years, occurred
earlier than Leydhecker suggested, even though most were being treated during that time. The level of
IOP appears to influence the rate of visual field loss. In one study of 177 untreated patients with COAG
comparing the mean age of presentation with the degree of field loss, it was estimated that untreated
disease is likely to progress from early to end-stage visual field loss in 14.4 years at pressures of 21 to
25 mm Hg, in 6.5 years at pressures of 25 to 30 mm Hg, and in 2.9 years at pressures greater than 30
mm Hg (17). Furthermore, once field loss has occurred, further damage tends to progress more rapidly
than in the fellow undamaged eye exposed to the same IOP, which appears to reflect the increased
susceptibility of the damaged eye (18, 19 and 20).
The “natural” course of NTG was evaluated in the Collaborative Normal-Tension Glaucoma Study
(CNTGS) during the time before randomization and in patients assigned not to receive treatment (21).
About one third of patients showed confirmed localized visual field progression at 3 years, and about
one half showed further deterioration at 7 years. The change was typically small and slow, often
insufficient to measurably affect the mean deviation index, and there was tremendous variability in
progression rates, with women, older individuals, or those with a disc hemorrhage, or history of
migraine having a greater risk for progression. In the Early Manifest Glaucoma Trial, 76% of patients
demonstrated progression on specific optic nerve or visual field endpoints after an average 4 years of
follow-up (22).
Identifying Patients and Those at Increased Risk
COAG has no associated symptoms or other warning signs before the development of advanced visual
field loss. It is for this reason that public and family physician awareness programs are needed to ensure
that high-risk patients receive glaucoma assessment examinations by eye care specialists. Such programs
must use the systemic and ocular risk factors discussed in Chapter 9, which are commonly associated
with the disease, to identify those segments of the population requiring the closest attention. In addition,
once a patient has been found to have persistent IOP elevation (the most significant risk factor) but no
apparent optic nerve head or visual field damage, the additional risk factors must be considered by the
physician when trying to decide which of these individuals require closer observation or the initiation of
therapy before definite damage occurs. (In Chapters 9 and 10, the risk factors for developing COAG and
the use of these factors in determining the frequency of periodic eye examinations for detection of
glaucoma are discussed.)
CLINICAL DIFFERENCES BETWEEN NTG AND COAG
Chronic Open-Angle Glaucoma
Measured IOP greater than 21 mm Hg before treatment is generally considered elevated. Even though an
elevated IOP is only one of several risk factors for COAG, it is a causative risk factor, and most studies
agree that it is the single most important risk factor.
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Central Corneal Thickness
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The cornea is typically normal in COAG. Measurement of central corneal thickness with ultrasonic or
optical methods is helpful in interpreting the accuracy of applanation tonometry readings as well as in
assisting with estimating the risk for progression. Published evidence regarding the value of central
corneal thickness for prognostic information is strong in the case of patients with ocular hypertension
but is considerably weaker in patients with established glaucoma (23). Hence, in patients with
established COAG, a thinner cornea (if structurally normal) signifies that the “true” IOP is higher than
measured but that the risk for progression may or may not be higher.
Anterior Chamber Angle
By traditional definition, the anterior chamber angle in eyes with COAG is open and grossly normal on
gonioscopic examination (Chapter 3). Preliminary studies, however, suggest that these patients may
have more iris processes, a higher insertion of the iris root, more trabecular meshwork pigmentation
(24), and a greater-than-normal degree of segmentation in the pigmentation of the meshwork (25).
Optic Nerve Head
The appearance of the optic nerve head and peripapillary retina is the single most important clinical
feature in establishing the presence of glaucomatous damage. A helpful early finding is defects in the
retinal nerve fiber layer, which may be a sign of glaucomatous optic atrophy before apparent changes
are seen in the nerve head (26). Other early findings include enlargement of the optic dose cup, thinning
or saucerizing of the neural rim, disc hemorrhages, and peripapillary atrophy (as explained in Chapter
4).
Visual Abnormalities
Central visual acuity, as measured by standard clinical tests, typically remains normal until there is
marked visual field loss within the central visual field. How little remaining central visual field is
necessary to retain excellent visual acuity is often remarkable. Therefore, in cases where visual acuity is
reduced while significant portions of the central 5 to 10 degrees are retained, other nonglaucomatous
causes for visual acuity loss should be considered. Preliminary evidence, however, suggests that more
subtle measures of vision dysfunction, such as contrast sensitivity, color vision, and motion perception
(discussed in Chapter 6), may one day be useful as early indicators of visual dysfunction before the
development of typical visual field loss. Once typical glaucomatous damage to the visual field has been
documented in one eye, there is a high incidence of subsequent field loss in the fellow eye. The latter
was reported to be 29% in 31 patients followed up for 3 to 7 years (27), and 25% of 104 individuals after
5 years of follow-up in another series (28).
Normal-Tension Glaucoma
As noted earlier, some investigators consider NTG to be clearly distinguishable from the high-tension
form of COAG, but others do not. COAG likely is a spectrum of disorders in which elevated IOP is the
most influential causative factor at one end, whereas other IOP-independent factors that influence
glaucomatous optic atrophy predominate at the other end. In any case, clinical differences between NTG
and COAG are considered here.
Optic Nerve Head
Some investigators have found the neural rim to be significantly thinner in patients with NTG, especially
inferiorly and inferotemporally, than in other patients with COAG who have similar total visual field
loss (7). Other studies have revealed less striking differences, with considerable overlap between
hightension glaucoma and NTG. A study of morphologic characteristics of the optic nerve head in hightension glaucoma and NTG eyes showed no significant difference in any parameter as measured by laser
scanning ophthalmoscopy (29).
Some studies have found that optic disc hemorrhages were more prevalent in the group with NTG,
raising the possibility of vascular disease as another causative factor in these patients (7). The retinal
nerve fiber layer has also been compared between patients with NTG and those with COAG, with the
former having more localized defects, closer to the macula, and the latter more diffuse defects (30, 31
and 32).
Visual Fields
Differences have also been reported in the nature of visual field loss between patients with NTG and
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those with COAG who have similar optic nerve damage. In general, patients with NTG appear to have
deeper, more localized scotomas (33). There are also conflicting reports regarding the proximity of
scotomas to fixation between the two groups, which may relate to the testing methods. One study found
a significantly greater rate of progressive visual field loss in NTG (34), and another revealed a
difference in the pattern of the progression, with the patients with high-tension glaucoma initially
increasing mainly in area and later in depth, whereas the increases in area and depth remained in
constant proportion in patients with NTG (35).
Although NTG, by definition, is distinguished from high-tension COAG by an IOP that is never
recorded to exceed 21 mm Hg, the pressures do tend to be higher than those in the general healthy
population (36). A number of studies have revealed a significant influence of IOP on the progression of
visual field or neuroretinal rim damage in NTG (37, 38), although another study showed no significant
difference in IOP between patients with and those without field progression (39). In some studies of
patients with NTG and asymmetric IOP, the visual field loss was typically worse in the eye with the
higher pressure (40, 41). However, a more rigorous, prospective evaluation of 190 patients with NTG in
the Low-Pressure Glaucoma Treatment Study found IOP asymmetry to be unrelated to visual field
asymmetry (42).
A randomized trial of treated versus untreated patients with NTG has convincingly shown that an IOP
reduction of at least 30% is associated with protection of visual field and nerve
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status, thus validating the concept that IOP is a contributory factor in the optic neuropathy of NTG. The
bulk of the evidence, therefore, suggests that IOP in the high-normal range is a causative factor in NTG,
although other factors are also involved. In making the diagnosis of NTG and in the management of
these patients, it is important to know the diurnal variation in IOP to confirm that their pressures are
consistently below 21 mm Hg before therapy and are staying within the target level while on treatment.
One study suggested that patients with NTG have wider diurnal fluctuations than the general healthy
population (36), although other investigators found no significant difference in diurnal variation of IOP
or of aqueous humor flow or resistance to outflow (43, 44).
It is also important to note that IOP spikes may occur at night, and therefore IOPs measured during
office hours may miss nocturnal spikes in many patients (7). The concomitant changes of nocturnal
orbital blood pressure and IOP may affect blood perfusion to the optic nerve head differently in
glaucomatous eyes, compared with healthy eyes, and this also might affect the susceptibility of the optic
nerve to damage. When a patient has progressive visual field loss or optic disc or retinal nerve fiber
layer damage in the presence of an apparently well-controlled IOP during the day, it is appropriate to
consider that the nocturnal IOP (during sleep) may be elevated (45). Obtaining 24-hour IOP
measurements is often difficult if not impossible. Furthermore, even if this were possible, whether the
nighttime readings reflect the true IOP during sleep is unclear.
Ocular Vascular Abnormalities
As noted earlier in this section, additional causative factors may relate to the architecture of the lamina
cribrosa and the vascular perfusion of the optic nerve head. Drance and coworkers (46, 47) described
two forms of NTG: (a) a nonprogressive form, which is usually associated with a transient episode of
vascular shock, and (b) a more common progressive form, which is believed to result from chronic
vascular insufficiency of the optic nerve head. Various cardiovascular and hematologic abnormalities
have been described, which might account for both forms (48). Reported associated findings include
hemodynamic crises, reduced diastolic ophthalmodynamometry levels and ocular pulse amplitudes,
bilateral complete occlusion of the internal carotid artery with reversed ophthalmic artery flow, focal
arteriolar narrowing around the optic nerve, and increased vascular resistance of the ophthalmic artery
by color Doppler analysis (46, 47, 49, 50, 51 and 52). It is wise to consider untreated glaucomatous optic
neuropathy to be a progressive rather than a quiescent process.
Systemic Vascular Abnormalities
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Reports of alterations in systemic blood pressure are conflicting. However, patients with NTG have
significantly greater nocturnal blood pressure drops than healthy persons (53), as well as elevated
diastolic blood pressure (54). Twenty-four-hour electrocardiographic monitoring has shown significantly
greater asymptomatic myocardial ischemia in patients with NTG (45%) than in healthy individuals
(5%), with many ischemic episodes occurring during the night (55). Visual-evoked responses during
stepwise artificially increased IOP were significantly different between patients with NTG and those
with high-tension COAG, suggesting a greater lack of autoregulation of optic nerve head circulation in
the former group (56). In patients with NTG whose disease is progressing despite seemingly normal
IOP, it may be appropriate to request 24-hour blood pressure monitoring, where available, to look for
dips in nocturnal blood pressure and alterations of perfusion pressure to the optic nerve.
Patients with NTG were noted to have an increased frequency of headaches with or without migraine
features (57). Another study failed to confirm this association (58), whereas a third investigation found
that patients with NTG and headaches had significantly lower IOP than patients with NTG and no
headaches, suggesting a subset within this group of patients (59). An abnormally reduced blood flow in
the fingers, especially in response to exposure to cold, has also been reported (60, 61). Other
investigators again found two subsets of COAG: (a) a smaller one with vasospastic finger blood flow
measurements and a highly positive correlation between visual field loss and IOP and (b) a larger group
with disturbed coagulation and biochemical measurement, suggestive of vascular disease, with no
correlation between field and highest IOP (62). A study of peripheral vascular endothelial function in
patients with NTG found impaired acetylcholine-induced peripheral endothelium-mediated vasodilation
in comparison with healthy age- and sex-matched controls (63), and a polymorphism of the endothelin
receptor type A gene has been associated with NTG (64). The bulk of the observations, therefore,
suggest that vasospastic events are involved in the mechanism of at least some forms of NTG. (The
therapeutic implications of this are discussed at the end of this chapter.)
Hematologic abnormalities reported to be associated with NTG include increased blood and plasma
viscosity and hypercoagulability (e.g., increased platelet adhesiveness and euglobulin lysis time) (41, 46,
65). Other studies, however, have revealed no statistically significant abnormalities in coagulation tests
or in vascular or rheological profiles (66, 67). Hypercholesterolemia is reported to be higher among
patients with NTG (68). Magnetic resonance imaging in patients with NTG has revealed an increased
incidence of diffuse cerebral ischemia, which may be further evidence for a vascular etiology (69, 70).
There is also some evidence that immune mechanisms may play a role in the mechanism of NTG. In one
study, 30% of the patients had one or more immune-related diseases, compared with 8% in a matched
group of patients with ocular hypertension (71). Additional support for an immune mechanism includes
the increased incidence of paraproteinemia and autoantibodies, such as antirhodopsin antibodies and
antiglutathione-S transferase (a retinal antigen) antibodies, in patients with NTG (72, 73 and 74). There
is also a report of postmortem histopathologic findings in a patient with NTG who had monoclonal
gammopathy and serum immunoreactivity to retinal proteins. Immunoglobulin G and A deposition was
noted in the ganglion cells and in inner and outer nuclear layers of the retina, and evidence of apoptotic
cell death was noted in the ganglion cell and inner nuclear layers of the retina (75).
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DIFFERENTIAL DIAGNOSIS OF NORMAL-TENSION GLAUCOMA
The differential diagnosis of NTG is summarized in Table 11.1 and should include wide diurnal IOP
fluctuations in which high pressures are occurring at times when they are not being recorded. Other
patients may have once had high pressures that caused damage that have since spontaneously
normalized. One example of this is pigmentary glaucoma, in which the IOP often improves with
increasing age or where a significant exposure to steroid medications in the past was associated with
undiagnosed secondary glaucoma-produced damage that stabilized once steroid use was stopped (76).
Another situation to distinguish from NTG is the case of advanced optic atrophy and visual field loss, in
which even mid-to-low pressures may be associated with or can cause further progressive damage. It is
also important to rule out nonglaucomatous causes of disc and field changes (discussed in Chapters 4
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and 5 and summarized in Table 11.1), and to consider the clinical scenarios when one may want to order
neuroimaging (computed tomography or magnetic resonance imaging of the orbit and chiasm) or other
studies (e.g., carotid Doppler, orbital B scan) to rule out these disorders (Table 11.2).
Adjunctive Tests
Numerous tests have been studied to find additional prognostic indicators of COAG. Although none of
these has yet been clearly proven to be of clinical value, the physician should be familiar with some of
the more frequently discussed adjunctive tests.
Tonography
This procedure and its limitations as a clinical tool in the diagnosis of COAG are discussed in Chapter 3.
Table 11.1 Differential Diagnosis of Normal- Tension Glaucoma
Congenital Disorders
Optic nerve anomalies, including coloboma, pits, oblique insertion
Autosomal dominant optic atrophy (Kjer type)
Acquired Disorders
History of steroid use by any route that may have led to elevated IOP
History of trauma or surgery that may have led to elevated IOP
Hemodynamic crisis
Methyl alcohol poisoning
Optic neuritis
Arteritic ischemic optic neuropathy
Nonarteritic ischemic optic neuropathy
Compressive lesions of the optic nerve and tract (e.g., meningioma, vascular lesion)
Trauma
Wide diurnal fluctuation in IOP
Table 11.2 Relative Indications to Perform Neuroimaging Evaluation in Normal-Tension
Glaucoma
General
Age <50y
New onset or increased severity of headaches
Localizing neurologic symptoms other than migraine
Neurologic visual abnormalities
Ocular
Color vision abnormalities
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Pallor of the remaining neuroretinal rim
Highly asymmetric cupping
Lack of disc and visual field correlation
Visual field defect respecting the vertical (midline)
Provocative Tests
These tests are largely of historical value, and the interested reader is referred to the fourth edition of
this text for a more detailed discussion with references.
Water Provocative Test
Drinking a large quantity of water in a short period of time will generally lead to a rise in the IOP. On
the basis of the theory that glaucomatous eyes have a greater pressure response to water drinking, a
“provocative” test was developed for the early detection of COAG. The test has little diagnostic value.
Dilatation Provocative Tests
These tests are used primarily in eyes suspected of having potentially occludable anterior chamber
angles (see Chapter 12). However, cycloplegics and mydriatics have also been studied with regard to
their influence on open-angle forms of glaucoma. These studies have not provided clinically useful
diagnostic tests, but a few points can be gleaned from them. Patients with COAG are more likely to have
a significant rise in IOP with strong cycloplegics (such as cyclopentolate, 1%; atropine, 1%;
homatropine, 5%; or scopolamine, 0.25%) if they are undergoing long-term miotic therapy. The
mechanism of the pressure response to strong cycloplegics is thought to include inhibition of the miotic
effect and direct inhibitory action on the ciliary muscle. In some cases, the postdilation IOP spike can be
marked.
The mydriatic action of cycloplegic-mydriatic agents or a mydriatic, such as phenylephrine, is also
thought to be a cause of elevated IOP in some eyes with open anterior chamber angles that are not
treated with miotics. This occurs only when an associated shower of pigment is in the anterior chamber.
The mechanism is thought to be temporary obstruction of the trabecular meshwork by pigment granules.
This occurs predominantly in eyes with the exfoliation syndrome or pigmentary glaucoma but may also
occur in some cases of COAG with heavy pigmentation in the anterior chamber angle.
Other Adjunctive Tests
The tendency of patients with COAG, as well as a certain percentage of the general population, to
respond to topical steroid therapy with an IOP rise has also been evaluated as a predictive
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test for COAG. However, steroid responsiveness has been found to correlate poorly with risk for COAG.
PROPOSED MECHANISM OF COAG
Mechanisms of Obstruction and Aqueous Outflow
As with virtually all forms of glaucoma, elevation of the IOP in COAG is due to obstruction of aqueous
outflow. However, the precise mechanisms of outflow obstruction in this condition remain poorly
understood despite having been studied intensively.
Histopathologic Observations
The most likely source for the eventual explanation of aqueous outflow obstruction in COAG lies in the
study of histopathologic material and molecular biology (see Chapters 1 and 10). However, the
interpretation of histopathologic findings must consider additional influences, such as age, the secondary
effects of prolonged IOP elevation, the alterations that medical and surgical treatment of the glaucoma
might have induced, and artifacts created by tissue processing.
Influence of Aqueous Humor
Growing evidence shows that abnormal constituents of the aqueous humor may adversely affect the
outflow structures, increasing resistance to outflow. Transforming growth factors (TGFs) are a family of
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multifunctional polypeptides with several cellular regulatory properties, including inhibition of epithelial
cell proliferation, induction of extracellular matrix protein synthesis, and stimulation of mesenchymal
cell growth. The aqueous humor of patients with COAG has a significantly greater amount of TGF-(ß2
than that of healthy individuals (77). Abnormal levels of TGF-ß2 in the aqueous of patients with COAG
may decrease the cellularity of the trabecular meshwork and promote a buildup of excessive amounts of
extracellular matrix materials with subsequent increased resistance to aqueous outflow.
Alterations of the Trabecular Meshwork
Grant demonstrated that the largest proportion of resistance to aqueous outflow in enucleated human
eyes could be eliminated by incising the trabecular meshwork (78). Since then, a number of studies have
demonstrated that the site of maximum resistance in the meshwork appears to be the juxtacanalicular
tissue and inner wall of the Schlemm canal (79). The most characteristic structural change in the
juxtacanalicular tissue is an increase in extracellular matrix and an accumulation of “plaque material.”
This material derives from thickened sheaths of elastic fibers, although the exact composition remains
unknown (77).
Stress-Response Markers
Myocilin, the first gene to be identified as mutated in COAG, appears to be produced in the eye in
greater amounts during times of stress. It is present in increased amounts in organ and cell culture
experiments after undergoing dexamethasone treatment, oxidative stress, stretching, and treatment with
TGF-ß (80). Another class of stress-induced proteins studied is heat-shock proteins, such as aBcrystallin. A study of donor eyes with COAG demonstrated differences in staining of two potential
stress-response markers, aB-crystallin and myocilin, in trabecular meshwork of glaucomatous eyes
(COAG, exfoliative glaucoma, NTG) in comparison with age-matched controls (81). These proteins
localized to many more regions of the meshwork and appeared more intense than in healthy eyes,
regardless of the type or clinical severity of glaucoma.
Endothelial cells lining the trabeculae appear to be more active in COAG than in normotensive eyes and
are reported to show proliferation with foamy degeneration and basement membrane thickening (82).
The cellularity of the trabecular meshwork in eyes with COAG is lower than that in nonglaucomatous
eyes, but the rate of decline with age is similar in the two groups (83). A reduced frequency of actin
filaments (contractile proteins) in trabecular endothelium has also been demonstrated in eyes with
COAG (84). Cross-linked actin networks, which alter the function of trabecular cells, were found in
higher levels and increased more in response to dexamethasone in glaucoma eyes than in healthy control
eyes in tissue culture (85).
Intertrabecular spaces, as might be anticipated from the general thickening of the trabeculae, are
narrowed (86). In addition, they may contain red blood cells, pigment, and dense amorphous material
(82). Glycosaminoglycans are reported to be more abundant in the meshwork of human eyes with
COAG (87, 88). However, hyaluronic acid has been shown to be decreased in the trabecular meshwork
of eyes with COAG, and the loss of its surface-active properties may influence aqueous outflow
resistance (89). Perfusion of cationized ferritin in enucleated eyes of patients with COAG suggests that
the outflow obstruction is segmental (90).
Several observers have noted that juxtacanalicular connective tissue just beneath the inner wall
endothelium of the Schlemm canal contains a layer of amorphous, osmophilic material (91). This has
been described as moderately electrondense, nonfibrillar material with characteristics of basement
membrane and curly collagen and cytochemical properties of chondroitin sulfate protein complex (92,
93). However, the concentration of electron-dense materials, although significantly higher than that of a
healthy control participant, is not thought to be enough to account for the outflow reduction
characteristic of COAG (91). Matrix vesicles, representing extracellular lysosomes, a sheath material
from subendothelial elastic-like fibers, the extracellular glycoprotein fibronectin, and elastin have also
been found in abnormal amounts in the juxtacanalicular connective tissue of eyes with COAG (94, 95,
96 and 97). These patients also differ from the healthy population in their collagen binding of plasma
fibronectin (98). A study of glycosaminoglycan composition in the juxtacanalicular connective tissue of
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COAG eyes and age-matched healthy eyes demonstrated that the juxtacanalicular connective tissue in
healthy eyes is stratified with hyaluronic acid as the predominant glycosaminoglycan in layers closest to
the endothelium of the Schlemm canal (99). In COAG eyes, hyaluronic acid was depleted in all layers
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within the juxtacanalicular connective tissue, and accumulation of chondroitin sulfate was significantly
higher in the juxtacanalicular connective tissue, possibly accounting for the increased outflow resistance
in these eyes.
Pores and giant vacuoles are found in the inner wall endothelium of the Schlemm canal in healthy eyes
and are thought to be related to aqueous transport. In eyes with COAG, the giant vacuoles have been
found in most studies to be decreased or absent. Pore density has also been shown to be reduced and
more unevenly distributed in COAG eyes than in healthy eyes (100). In addition, cul-de-sacs, which are
described as terminations of aqueous channels, are markedly reduced in eyes with COAG (101).
In a study of the trabecular meshwork and optic nerve from 26 eyes of 14 donors, increasing severity of
optic nerve damage (as quantitated by axon counts) was significantly correlated with an increase in the
amount of sheath-derived plaque material in the juxtacanalicular connective tissue (102).
Collapse of the Schlemm Canal
Collapse of the Schlemm canal will also increase resistance to aqueous outflow and has been proposed
as a mechanism of outflow obstruction in COAG. The collapse represents a bulge of trabecular
meshwork into the canal, which might result from alterations in the meshwork or relaxation of the
ciliary muscle. In support of this theory, some histopathologic studies have revealed a narrowed
Schlemm canal with adhesions between the inner and outer walls (82). A mathematical model of the
Schlemm canal, however, tentatively suggests that resistance to aqueous outflow is in the inner wall of
the canal and is not caused by a weakening of the trabecular meshwork with a resultant collapse of the
Schlemm canal alone (103).
In interpreting the histologic findings in the juxtacanalicular connective tissue and Schlemm canal, it is
advisable to take into account a certain amount of segmental variability and to examine at least three
quadrants per eye (104).
Alterations of the Intrascleral Channels
Alterations of the intrascleral channels could also be a mechanism of increased resistance to aqueous
outflow in COAG. Histopathologic observations have revealed attenuation of the channels, which may
be due to a swelling of glycosaminoglycans in the adjacent sclera (105). Krasnov (106) suggested that
intrascleral blockage may be the mechanism of outflow obstruction in approximately half of the eyes
with COAG. However, this theory was not supported by a study in which removal of tissue overlying
the Schlemm canal failed to improve outflow facility until the canal was actually entered (107).
Corticosteroid Sensitivity
As previously noted, there is evidence that patients with COAG are unusually sensitive to
corticosteroids and that this steroid sensitivity may be related to the abnormal resistance to aqueous
outflow. This discussion first considers the evidence for the increased sensitivity and then looks at
theories of how this may influence outflow.
Topical Corticosteroid Response
General population studies have been performed in which a potent topical corticosteroid, such as
betamethasone, 0.1%, or dexamethasone, 0.1%, was given three to four times daily for 3 to 6 weeks.
These studies found that a substantial proportion of individuals respond with variable degrees of IOP
elevation. The studies have differed considerably, however, with regard to many important aspects of
this pressure response. For example, the distribution of pressure responses in the general population was
found in some studies to be trimodal, with approximately two thirds of participants having a low
response (usually defined as an increase in IOP of less than 5 mm Hg), one third showing an
intermediate response (increase of 6 to 15 mm Hg), and 4% to 5% having an increase greater than 15
mm Hg (108, 109 and 110). Another study, however, could not confirm the trimodal concept (111), and
when the topical corticosteroid test was repeated in the same population, individuals did not always have
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the same response each time (112).
COAG populations have more individuals with a high IOP response to topical corticosteroids. The
actual reported percentage of high responders, however, varies according to the criteria used to define
this group. Reports also differ as to whether patients with ocular hypertension do or do not have a
greater incidence of high response than the general population (113, 114). The topical corticosteroid
response, however, has not been found to be a useful prognostic indicator for COAG (115, 116).
Inheritance of the topical corticosteroid response and how this may relate to COAG have been matters of
particular controversy. Becker postulated an autosomal recessive mode for the corticosteroid response
and suggested that the gene is closely related or identical to that for COAG, which he thought had an
autosomal recessive inheritance (108, 117). Armaly agreed that the two conditions might be genetically
related but proposed a polygenetic inheritance for COAG, with the gene for the topical corticosteroid
response being one of the genes involved (110). Results of additional studies were consistent with a
genetic basis for the topical corticosteroid response but could confirm neither the recessive mode nor
even a relationship to glaucoma (114, 118). Still other investigators could not even substantiate that the
corticosteroid response was entirely genetic. A twin-heritability study of monozygotic and like-sex
dizygotic twins revealed a low estimate of heritability that did not support a predominant role of
inheritance in the response to corticosteroids and suggested that nongenetic factors play the major role
(111, 119, 120 and 121). A study that further confuses the role of steroids in COAG found that eyes with
unilateral angle-closure glaucoma or angle recession also respond to topical corticosteroids with a higher
pressure rise in the involved eye than in the fellow eye, which had not had angle closure or trauma (122,
123). These observations suggest that topical corticosteroid responsiveness is multifactorial.
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Relationship of Intraocular Pressure to Corticosteroid Sensitivity
Investigators have tried to explain if or why patients with COAG are unusually sensitive to
corticosteroids.
Hypothalamic-Pituitary-Adrenal Axis Theory
An abnormal response of the hypothalamic-pituitary-adrenal axis in patients with COAG, and possibly
in other forms of glaucoma, may be related to alterations in aqueous humor dynamics in response to
corticosteroids (124, 125).
Cyclic-Adenosine Monophosphate Theory
It may be that corticosteroids influence the IOP by altering cyclic-adenosine monophosphate.
Corticosteroids have a permissive effect on the ß-adrenergic stimulation of adenyl cyclase, the enzyme
responsible for the synthesis of cyclic-adenosine monophosphate (126). How this relates to aqueous
humor dynamics is uncertain, although patients with COAG and high topical steroid responders appear
to be unusually sensitive to cyclic-adenosine monophosphate.
Glycosaminoglycans Theory
It has also been proposed that IOP elevation associated with corticosteroid sensitivity may be related to
glycosaminoglycans in the trabecular meshwork (127). When polymerized, glycosaminoglycans become
hydrated, swell, and obstruct aqueous outflow. Catabolic enzymes, released from lysosomes in the
trabecular cells, depolymerize the glycosaminoglycans. Cortico — steroids stabilize the lysosome
membrane, preventing release of these enzymes and thereby increasing the polymerized form of
glycosaminoglycans and the resistance to aqueous outflow.
Phagocytosis Theory
The effect of steroids on IOP may be related to the phagocytic activity of endothelial cells lining the
trabecular meshwork. These cells are normally phagocytic, and they may function to “clean” the
aqueous of debris before it reaches the inner wall endothelium of the Schlemm canal. Failure to do so
might result in a buildup of material that could account for the amorphous layer in the juxtacanalicular
connective tissue (as previously described). Corticosteroids suppress phagocytosis, and it may be that
the trabecular endothelium in patients with COAG is unusually sensitive, even to endogenous
corticosteroids (128).
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Mechanism of Optic Neuropathy
Histopathologic Observations
Axon loss in eyes with COAG has been reported to be associated with increasing connective tissue in
the septa and surrounding the central retinal vessels, including increased amounts of types IV and VI
collagen (129). The total number of capillaries and the density of capillaries decreased with loss of
axons. Arteriosclerotic changes were more common in glaucomatous eyes than in age-matched control
eyes.
Immunologic Studies
A number of reports suggest an immunoregulatory mechanism in the pathogenesis of COAG, at the
level of the meshwork, ganglion cell bodies and optic nerve axons, retinal vessels, and lamina cribrosa.
The roles of the immune system in glaucoma have been described as either neuroprotective or
neurodestructive. It has been proposed that a critical balance between beneficial protective immunity
and harmful sequelae of autoimmune neurodegenerative injury (such as heat-shock proteins) determines
the ultimate fate of retinal ganglion cells in response to various stressors in patients with glaucoma. The
Canadian Glaucoma Study reported that an elevated anticardiolipin antibody is associated with
progression of COAG (130). Anticardiolipin antibody is one of the antiphospholipid antibodies found in
elevated levels in patients with acquired thrombotic syndromes (131, 132).
Blood Flow
Abnormalities of blood flow to the posterior segment of the eye in COAG have been shown by using
color Doppler imaging, fluorescein angiography, laser Doppler flowmetry, and pulsatile ocular blood
flow measurements (133, 134, 135, 136, 137, 138, 139, 140 and 141). Rheological studies have also
demonstrated differences in red cell aggregability, increased plasma viscosity, and activation of the
clotting system in patients with COAG compared with controls (65, 142, 143). Altered autoregulation of
blood flow in the optic nerve and retinal circulation has also been demonstrated (144, 145).
Changes in the retrobulbar hemodynamics also appear to occur with age. Color Doppler imaging
analysis of the ophthalmic, central retinal, and nasal and temporal posterior ciliary arteries in healthy
men and women demonstrated age-related alterations in hemodynamics, similar to those seen in patients
with glaucoma, suggesting that these age-related changes may contribute to an increased risk for
glaucoma (146).
There is also evidence that the choroidal circulation is compromised in COAG (147, 148), which is
supported by electroretinographic data demonstrating outer retinal damage in eyes with glaucoma (149).
Apoptotic Susceptibility of Ganglion Cells
Ganglion cells appear to die by apoptosis in experimental glaucoma (150). This may relate to a
multiplicity of factors (Fig. 11.1). Clinically, some evidence is related to excitotoxic cell death from
accumulation of glutamate and an imbalance of proteases that modulate the extracellular matrix milieu
in the retina (151, 152).
Possible Infectious Susceptibility
In a study of 32 patients with COAG, 9 with exfoliative glaucoma, and 30 age-matched control patients
with anemia, upper gastrointestinal endoscopy was performed to evaluate macroscopic abnormalities
and gastric mucosal biopsy specimens were analyzed for the presence of Helicobacter pylori infection
(153). Approximately 88% of the patients with COAG and exfoliative glaucoma had histologically
confirmed H. pylori infection, compared with 47% among controls. Patients with
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glaucoma also exhibited abnormal gastric mucosa, antral gastritis, and peptic ulcer disease. Not all
studies have found this correlation (154).
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Figure 11.1 Diverse insults can lead to retinal ganglion cell death. These include IOP-related and nonIOP-related factors. (Reproduced from Libby RT et al. Complex genetics of glaucoma susceptibility.
Annu Rev Genomics Hum Genet. 2005;6:15-44, with permission).
Cerebrospinal Fluid Pressure
The lamina cribrosa is located between two pressurized compartments, intraocular space and the
subarachnoid space posteriorly (see Chapter 4). The pressure difference between these two spaces has
been termed the “translaminar pressure.” In this context, a reduced cerebrospinal fluid (CSF) pressure
would exert the same effect as an increase in IOP. Emerging evidence suggests that the translaminar
pressure may play an important role in glaucomatous optic neuropathy (155, 156 and 157). In these
studies, the measured CSF pressure was significantly lower in participants with COAG compared with
controls. In addition, CSF pressure was lower in participants with NTG, compared with those who had
COAG associated with elevated IOP. These data, although preliminary, suggest that the dynamic
interplay between these fluid spaces may play a role in glaucoma and may help explain why some
individuals with normal IOP may develop glaucoma and others with elevated IOP may not.
MANAGEMENT
General Principles of Management
The principles of when and how to treat patients with COAG are discussed in Chapter 27. In brief, it is
important to establish a target IOP range for both eyes of the patient—that is, an IOP range in which
there will presumably be no further anticipated optic nerve damage. This begins with a detailed history,
complete examination, and appropriate testing, after which the target IOP is set on the basis of stage of
glaucomatous damage and risk factors for progression (as discussed here). The target is a dynamic
concept that needs to be reevaluated at each visit. Once the target IOP range is set, it is achieved with
topical medication in most cases. If the target IOP range cannot be achieved despite maximum tolerable
medical therapy, argon or selective laser trabeculoplasty is usually indicated, followed by glaucoma
filtering surgery or other therapeutic maneuvers as deemed necessary. If optic nerve or visual field
progression occurs despite achieving the target IOP range, it may be necessary to revise the target IOP
downward and to consider IOP-independent mechanisms of the optic neuropathy.
Throughout the treatment course, the expense, inconvenience, and side effects of therapy should be
considered and an effective treatment plan that includes patient education, efficacy and toxicity of
therapy, and patient adherence should be established. A regimen of the least medication to achieve the
desired therapeutic response should be chosen for each eye of the patient. Follow-up evaluation should
be guided by the severity of the disease.
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Treatment of Normal-Tension Glaucoma
Although damage to the optic nerve head and visual field may progress even at low-normal pressures in
NTG, compelling evidence shows that IOP reduction from baseline values is effective. In the CNTGS,
57% of the patients achieved a 30% IOP reduction with topical medication, laser trabeculoplasty, or
both (158). The remaining 43% required filtering surgery. Although filtering surgery did not help in one
reported series (156), other surgeons have found that it may prevent progressive damage (159, 160, 161
and 162), and the CNTGS has confirmed the benefit of aggressive IOP reduction in these patients.
Despite the proven value of IOP reduction, some patients with NTG may have IOP-independent
mechanisms of glaucomatous optic neuropathy, and this must especially be considered when damage is
progressing with pressures in the single digits. An additional aspect of managing the patient with NTG
may be the treatment of any cardiovascular abnormality, such as anemia, hypotension, congestive heart
failure, transient ischemic attacks, and cardiac arrhythmias, to ensure maximum perfusion of the optic
nerve head (163).
Ultimately, the treatment of choice may prove to be therapy that directly protects and improves the
function of ganglion
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cells and the optic nerve head. A placebo-controlled 3-year study of the calcium-channel blocker
nilvadipine on visual field and ocular circulation in 33 patients with NTG suggested that blood flow to
the optic nerve and fovea was increased in the treated group. Furthermore, the mean negative slope in
mean deviation of the visual field over time was also less in the treated group (164). Other studies
involving patients with NTG receiving concurrent calcium-channel blocker therapy have demonstrated a
significant reduction in the rate of disc and field progression, compared with similar NTG groups who
were not receiving the concomitant therapy (165, 166).
KEY POINTS
COAG is the most common form of glaucoma worldwide. It has a familial tendency and is more
prevalent with increasing age, black race, myopia, and certain systemic diseases, such as diabetes
mellitus and cardiovascular abnormalities.
COAG is typically asymptomatic until advanced visual field loss occurs and is characterized by an
open, normal-appearing anterior chamber angle.
A clinical subset of COAG, NTG, has similar disc and field changes but pressures that remain in
the normal range without treatment. However, IOP is a contributing risk factor in both conditions,
with an increasing influence of IOP-independent factors in NTG. NTG is a diagnosis of exclusion,
and it is important to ensure that no atypical clinical features suggest nonglaucomatous causes of
optic nerve cupping.
The precise mechanism of increased resistance to aqueous outflow and to optic nerve damage in
COAG remains unclear, although continued research, especially in molecular biology, is
beginning to reveal answers to these complex processes.
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12 - Pupillary Block Glaucomas
> Table of Contents > SECTION II - The Clinical Forms of Glaucoma > 12 - Pupillary Block
Glaucomas
12
Pupillary Block Glaucomas
TERMINOLOGY
Primary versus Secondary Angle-Closure Glaucomas
Angle closure is characterized by apposition of the peripheral iris against the trabecular meshwork,
resulting in obstruction of aqueous outflow (see Chapter 7). The term glaucoma is used if there is
evidence of glaucomatous optic nerve damage. Traditionally, some forms of angle-closure glaucoma
have been referred to as primary angle-closure glaucoma because the mechanisms of angle closure were
not thought to be associated with other ocular or systemic abnormalities or because the mechanisms
were not well understood. Conditions that have been included in this group are pupillary block
glaucoma, plateau iris, and combined-mechanism glaucoma. Other forms of angle-closure glaucoma
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have been called secondary angleclosure glaucoma because of associated ocular or systemic
abnormalities or because of more apparent mechanisms of angle closure, such as contracting membranes
or inflammatory precipitates that pull the angle closed or space-occupying lesions that push it closed. As
continued research has expanded our knowledge of the associated abnormalities and mechanisms of
primary angle-closure glaucomas, the distinction between the primary and secondary forms has become
increasingly artificial, and the concept should probably be abandoned.
One example of how increased knowledge has progressively blurred the distinction between primary
and secondary glaucomas is seen in the condition called plateau iris (1, 2 and 3). This condition has
traditionally been included with the primary angle-closure glaucomas. However, because of information
regarding the mechanism of plateau iris, it is now considered to belong with the glaucomas associated
with disorders of the iris and ciliary body (see Chapter 17).
Figure 12.1 Pupillary block glaucoma. A functional block between the lens and iris (A) leads to
increased pressure in the posterior chamber (arrows) with forward shift of the peripheral iris and closure
of the anterior chamber angle (B).
In this chapter, we consider several forms of glaucoma that share the common mechanism of pupillary
block and that have traditionally been grouped as primary angle-closure glaucomas. The conditions that
have been called secondary angleclosure glaucomas are considered in subsequent chapters in this
section.
Pupillary Block Glaucoma
Pupillary block glaucoma is the most common form of angleclosure glaucoma. The initiating event is
thought to result from increased resistance to flow of aqueous humor between the pupillary portion of
the iris and the anterior lens surface (4), which is associated with mid-dilatation of the pupil (5). The
functional block produces increased fluid pressure in the posterior chamber, causing a forward shift of
the iris. Anterior movement of the peripheral iris can result in closure of the anterior chamber angle (4, 5
and 6) (Fig. 12.1). Four forms of pupillary block glaucoma may be distinguished on the basis of
symptoms and clinical findings (7): acute angle-closure glaucoma, subacute angle-closure glaucoma,
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chronic angle-closure glaucoma, and combined-mechanism glaucoma.
Acute Angle-Closure Glaucoma
In acute angle-closure glaucoma, the symptoms are sudden and severe, with marked pain, blurred vision,
and a red eye. The patient may also have nausea and vomiting.
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Subacute Angle-Closure Glaucoma
Subacute angle-closure glaucoma is thought to have the same pupillary block mechanism as the acute
form, but symptoms are mild or absent (8). The condition has also been called intermittent, prodromal,
or subclinical (9). Patients with subacute angle-closure glaucoma may have repeated subacute or
subclinical attacks before finally having an acute attack or developing peripheral anterior synechiae with
chronic pressure elevation (8).
Chronic Angle-Closure Glaucoma
In chronic angle-closure glaucoma, portions of the anterior chamber angle are permanently closed by
peripheral anterior synechiae, and the intraocular pressure (IOP) is chronically elevated (9, 10). The
synechial closure may result from a prolonged acute attack or repeated subacute attacks of angle-closure
glaucoma. A variation of this condition has been called shortening of the angle or creeping angle-closure
glaucoma (11, 12). It is important to look carefully for evidence of exfoliation syndrome, because
exfoliation can predispose to pupillary block in some patient populations (see Chapter 15).
Combined-Mechanism Glaucoma
In some eyes, the glaucoma appears to have open-angle and angle-closure mechanisms. The diagnosis is
usually made after an acute angle-closure glaucoma attack in which the IOP remains elevated after a
peripheral iridotomy, despite an open, normal-appearing angle.
EPIDEMIOLOGY
In most populations, pupillary block glaucoma is considerably less common than chronic open-angle
glaucoma. However, there is a reversal in the ratio of angle-closure and open-angle glaucoma cases
among Canadian, Alaskan, and Greenland Eskimos, with the former disorder occurring in approximately
0.5% of the general population and in 2% to 3% of those older than 40 years of age, with a predilection
for women (13, 14, 15 and 16). A similar observation was made in population studies from China,
Singapore, Mongolia, and South India and a mixed ethnic group in South Africa, in which the
prevalence of angleclosure glaucoma was 2.3%, compared with 1.5% for chronic open-angle glaucoma
(17, 18, 19 and 20). This prevalence of angle-closure glaucoma may be caused by a smaller corneal
diameter and anterior chamber depth and a thicker, more anteriorly placed lens in affected individuals
(21, 22 and 23). A study among Alaskan Eskimos also showed a rapid increase in hyperopia after age
50, reaching 71.5% in persons older than 80 years (24).
Studies of the anterior chamber angle in various populations provide an impression of the prevalence of
those at increased risk for pupillary block glaucoma. In two large studies, 5% to 6% of those screened
had suspicious anterior chamber angles, but only 0.64% to 1.1% were considered to have critically
narrow angles (25, 26). In a Vietnamese population residing in the United States, 8.5% had critically
narrow angles and were considered to be at high risk for occlusion (27).
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Figure 12.2 Pupillary block glaucoma (A) contrasted with the plateau iris syndrome (B). In the latter
situation, notice the relatively deeper central anterior chamber, the flat iris plane, patent iridectomy, and
bunching up of peripheral iris in the anterior chamber angle.
CLINICAL FEATURES
The diagnosis of pupillary block glaucoma has several facets. During the course of every ocular
examination, the physician must consider general risk factors in the medical history and look for
anatomic features that may predispose to angle closure. The gold standard examination is gonioscopy,
which is essential in identifying eyes with some form of angle closure or those at increased risk for
angle-closure glaucoma (i.e., occludable angles). In other situations, the patient may present with signs
and symptoms suggesting angle-closure glaucoma, and the correct diagnosis will depend on an
understanding of the symptoms, predisposing circumstances, physical findings of the disease, and the
differential diagnosis (Fig. 12.2). The various aspects of diagnosing potential or manifest pupillary block
glaucoma are considered in this chapter.
Risk Factors
General Features of Patients
Several factors influence the configuration of the anterior chamber angle and the risk for pupillary block
glaucoma.
Age
The depth and volume of the anterior chamber diminish with age (28), which may result from thickening
and forward displacement of the lens (29, 30). Consequently, the percentage of individuals with
critically narrow angles is higher in older agegroups. The prevalence of pupillary block glaucoma also
increases with age, although it may peak earlier in life, compared with chronic open-angle glaucoma.
One study found a bimodal pattern, with the first peak at ages 53 to 58 years and the second at 63 to 70
years (29). However, it can occur at any age, including rare cases in childhood (31).
Race
The relative prevalence of pupillary block glaucoma among all the glaucomas is increased in various
populations of Inuit and
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individuals with Far Eastern Asian extraction (13, 14, 15, 16, 17 and 18). Acute angle-closure glaucoma
is less common among blacks, but subacute or chronic angle-closure glaucoma is not uncommon and
appears to be a regularly missed diagnosis (32, 33 and 34). The explanation for this difference is
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uncertain. One study suggested that it might be caused by a thinner average lens thickness (33), although
another investigation revealed the anterior chamber depth in Nigerian blacks to be equivalent to that of
whites (35). The weaker response to mydriatics observed among African blacks could indicate that
darker irides are less able to exert the force that may lead to acute pupillary block (36). Angle-closure
glaucoma also has a reduced prevalence among American Indians and is often caused by a swollen lens
when it does occur in this group (34).
Sex
There is a statistically significant predominance of females in populations with pupillary block
glaucoma, which is probably because of the shallower anterior chamber among women in general (13,
14, 16, 28).
Refractive Error
The depth and volume of the anterior chamber are related to the degree of ametropia, with smaller
dimensions occurring in those with hyperopia (28). However, the presence of myopia does not eliminate
the possibility of angle-closure glaucoma because rare cases have been reported in such patients (37),
possibly indicting a spherical or anteriorly displaced lens or an increase in corneal curvature (38).
Family History
The potential for pupillary block glaucoma is generally believed to be inherited (see Chapter 8). In one
study, 20% of 95 relatives of patients with angle-closure glaucoma were thought to have potentially
occludable angles (39). However, aside from a few reported families in which many members developed
angleclosure glaucoma, the family history is not very useful in predicting a future angle-closure attack
(40).
Systemic Disorders
Researchers in one study found an inverse correlation between type 2 diabetes or an abnormal result on
a glucose tolerance test and the anterior chamber depth (41). The same investigators also suggested that
angle-closure glaucoma may be associated with an increased prevalence of denervation supersensitivity
to autonomic agonists (42).
Findings on Routine Examination
Certain observations during the course of a routine ocular examination can help to establish the potential
for angle closure.
Unless the patient has angle closure at the time of the examination, the IOP is usually normal. One
study, however, found a larger-than-normal amplitude in the diurnal IOP curve, which the investigators
thought might have prognostic value (43). Tonography also characteristically reveals normal outflow
facility before or between attacks, unless peripheral anterior synechiae are present (5).
Evaluation of Peripheral Anterior Chamber
Photogrammetric studies of all forms of angle-closure glaucoma have revealed anterior chamber depths,
volumes, and diameters that are smaller than those of matched controls (44). Anterior chamber depth
and volume have also been shown to have diurnal variation, with lower values in the evening (45),
although a correlation between diurnal variations of chamber depth and IOP is not clear. In any case, the
most important step in the diagnosis of potential or manifest angle-closure glaucoma is to evaluate the
anterior chamber depth and especially the configuration of the anterior chamber angle. Although this is
best accomplished by gonioscopy, there are preliminary screening measures that may be useful in some
situations and techniques of quantifying the anterior chamber depth.
Penlight Examination
When a slitlamp and goniolens are not available, the anterior chamber depth can be estimated with
oblique penlight illumination across the surface of the iris. With the light coming from the temporal side
of the eye, a relatively flat iris is illuminated on the temporal and nasal sides of the pupil, whereas an iris
that is bowed forward has a shadow on the nasal side (46) (Fig. 12.3).
Slitlamp Examination
The central anterior chamber depth may be estimated during examination with the slitlamp, and several
techniques for quantitating this parameter have been proposed (47, 48 and 49). However, the central
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anterior chamber depth only weakly correlates with the angle width (50), and the parameter of greater
diagnostic value in the context of angle-closure glaucoma is the peripheral anterior chamber depth. van
Herick and colleagues (51) developed a technique for making this estimation with the slitlamp by
comparing the peripheral anterior chamber depth to the thickness of the adjacent cornea (Figs. 12.4 and
12.5). This is commonly referred to as the van Herick technique. When the peripheral anterior chamber
depth is less than one fourth of the corneal thickness, the anterior chamber angle may be potentially
occludable.
Gonioscopy
When the peripheral anterior chamber depth is thought to be shallow (i.e., less than one fourth of the
corneal thickness by van Herick slitlamp examination), careful gonioscopic examination of the angle is
required. This is best accomplished with a Zeiss four-mirror lens or similar goniolens. A 180-or-moredegree closure of the angle (i.e., trabecular meshwork is not visible) constitutes an occludable angle, and
it is important to use compression gonioscopy to determine whether the closure is appositional or
synechial. The patient should be examined in a dark room and with the use of a short, narrow slit-beam
to avoid constricting the pupil and artifactually opening the angle. The examiner also should take care to
avoid extra pressure on the cornea so that the angle does not deepen artifactually. If necessary, the
goniomirror on the Goldmann three-mirror lens
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can be used to avoid artifactual deepening of the chamber angle. If the peripheral iris is prominent, or
the iris is very convex and it is difficult to see angle structures, it is often helpful to have the patient look
in the direction of the mirror being viewed so that a more accurate assessment of what angle structures
are visible can be made.
Figure 12.3 Oblique flashlight illumination as a screening measure for estimating the anterior chamber
depth. A: With a deep chamber, nearly the entire iris is illuminated. B: When the iris is bowed forward,
only the proximal portion is illuminated, and a shadow is seen in the distal half.
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Figure 12.4 The slitlamp technique of van Herick and colleagues (51) is used for estimating the depth of
the peripheral anterior chamber (PAC) by comparing it with the adjacent corneal thickness (CT). The
PAC here is about 1 CT.
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Figure 12.5 Slitlamp photograph of the van Herick technique for estimation of peripheral anterior
chamber depth, showing the slit-beam on the cornea and iris.
Numerous grading systems have been proposed to correlate gonioscopic appearance with the potential
for angle closure. Scheie (52) proposed a system based on the extent of the anterior chamber angle
structures that can be visualized (Fig. 12.6). He observed a high risk of angle closure in eyes with grade
III or IV angles. Shaffer (1) suggested using the angular width of the angle recess as the criterion for
grading the angle and attempted to correlate this with the potential for angle closure (Fig. 12.7).
Figure 12.6 The Scheie gonioscopic classification of the anterior chamber angle, based on the extent of
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visible angle structures (52). A: Root of the iris. B: Ciliary body band. C: Scleral spur. D: Trabecular
meshwork. E: Schwalbe line.
Other investigators think that any single criterion cannot fully describe the anterior chamber angle.
Becker (53) proposed combining an estimation of the anterior chamber angle width and the height of the
iris insertion, whereas Spaeth (26) suggested an evaluation of three variables: angular width of the angle
recess, configuration of the peripheral iris, and apparent insertion of the iris root (Fig. 12.8). Whatever
system the clinician prefers to use to document the appearance of the anterior chamber angle, it is
important to pay close attention to these three aspects of the angle. One study proposed a relatively
simple method for measurement of the distance from the iris insertion to the Schwalbe line using a
reticule based in the slitlamp ocular during gonioscopy (54). The investigators called this technique
biometric gonioscopy and found that it correlated well with other measures of anterior chamber angle,
showing a higher degree of interobserver reliability than conventional gonioscopy. Additional features
of the angle should also be studied and documented, such as peripheral anterior synechiae and degrees
or abnormalities in pigmentation. One study found that patients with narrow angles may have a
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predominance of trabecular meshwork pigmentation in the superior quadrant, rather than the more
common inferior location, which the investigators thought might be caused by rubbing between the
peripheral iris and the meshwork (55).
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Figure 12.7 The Shaffer gonioscopic classification of the anterior chamber angle is based on the angular
width of the angle recess (1). The angular width and clinical interpretation are given for each of the
examples. A: Wide open (20 to 45 degrees): closure improbable. B: Moderately narrow (10 to 20
degrees): closure possible. C: Extremely narrow: closure possible. D: Partially or totally closed: closure
present.
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Figure 12.8 The Spaeth gonioscopic classification of the anterior chamber angle, based on three
variables (26). A: Angular width of the angle recess. B: Configuration of the peripheral iris. C: Apparent
insertion of the iris root.
Newer Techniques
Several newer forms of technology are being applied to evaluation of the anterior segment of the eye to
more accurately quantify the anterior chamber depth and related dimensions. The use of high-frequency
ultrasonography, referred to as ultrasound biomicroscopy, allows definition of the relationships of the
iris, posterior chamber, lens, zon

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